Treatment methods for patients with cancer associated with dysregulation of the MAPK and / or PI3K pathways

Abstract

1. A method of treating a patient having a cancer dysregulated in the MAPK and / or PI3K pathway, whereby the patient is administered an effective amount of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, or a pharmaceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present invention relates to methods of treating cancers associated with dysregulation of the MAPK and / or PI3K pathways. [Background technology]

[0002] Rat sarcoma (RAS) proteins are central regulators of cell proliferation and survival in normal and cancer cells. RAS activation activates effector pathways, most notably the mitogen-activated protein kinase (MAPK) pathway and the PI3 kinase (PI3K) pathway. See Pratilas CA et al., Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. Clin Cancer Res. 2010;16(13):3329-3334. The signaling cascade of the MAPK pathway includes Ras / Raf / MEK / ERK / RSK, while the signaling cascade of the PI3K pathway includes Ras / PI3K / PTEN / AKT / mTOR / S6K. See Steelman LS et al., Roles of the Raf / MEK / ERK and PI3K / PTEN / Akt / mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging (Albany NY). 2011;3(3):192-222. The activity of these pathways is regulated through feedback loops, demonstrating nonlinear and highly bidirectional signaling. See McCubrey JA et al., Mutations and deregulation of Ras / Raf / MEK / ERK and PI3K / PTEN / Akt / mTOR cascades which alter therapy response. Oncotarget. 2012;3(9):954-987.

[0003] Therapeutic single-agent pathway inhibition can be hampered by feedback loops to reciprocal pathways.In addition, dysregulation of components of these cascades through aberrant activation / inactivation has been linked to chemotherapy drug resistance and resistance to other pathway inhibitors, leading to poor clinical responses.

[0004] Neurofibromin 1 (NF1) is the gene that encodes the GTPase-activating protein neurofibromin, a negative regulator of the RAS pathway, which, when aberrant, may act as a prominent driver in cancer. Mutations and deletions in NF1 are common in sporadic cancers and are associated with increased cancer risk and drug resistance. In addition, germline mutations in the NF1 gene cause neurofibromatosis type 1, and affected patients are at increased risk for several different types of adult cancer, including breast cancer. NF1 gene variants are found in 2-4% of breast cancers, and shallow deletions of NF1 have been observed in 25% of sporadic breast cancers and correlated with higher tumor grade, tumor size, aggressive basal-like subtype, and poor outcome in the first decade. See Dischinger PS et al., NF1 deficiency correlates with estrogen receptor signaling and diminished survival in breast cancer. NPJ Br Cancer. 2018;4:29. Loss of NF1 increases Ras effector activation, resulting in increased extracellular signal-regulated kinase (ERK), v-akt murine thymoma viral oncogene homolog (AKT), and ribosomal protein S6 phosphorylation. See Kaul A et al., Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth. Neuro Oncol. 2015;17(6):843-853.

[0005] In addition, phosphatase and tensin homolog (PTEN) is a negative regulator of the PI3K pathway, and mutations or deletions of the PTEN gene contribute to cancer, poor disease outcomes, and germline Cowden syndrome. Tumors with low expression of PTEN or other cancer driver gene mutations, such as phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, are known to activate AKT. See Xing et al., Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and / or PTEN loss / PTEN mutation. Breast Cancer Res. 2019;21(1):78. Cancer patients with PIK3CA mutations, PTEN loss (or mutation), or AKT mutations have been included in several biomarker-driven studies, but no significant correlation between these gene mutations and tumor response has been identified. See Janku et al., Targeting the PI3K pathway in cancer: are we making headway? Nature Rev Clin Oncol. 2018;15:273-91, 2018;Rodon et al., Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol. 2013;10:143-53.

[0006] Furthermore, as a member of the RAS oncogene family, the Kirsten rat sarcoma virus (KRAS) gene is the most frequently mutated oncogene. KRAS mutations can cause continuous activation of the MAPK and PI3K pathways, which contribute to cancer growth, and are associated with poor prognosis and resistance to treatment. See Haigis KM. KRAS alleles: the devil is in the detail. Trends Cancer, 2017; 3(10):686-697;Zhuang R, et al., The prognostic value of KRAS mutation by cell-free DNA in cancer patients: A systematic review and meta-analysis. PLOS ONE. 2017;12(8):e0182562. In addition, abnormalities in both the MAPK and PI3K pathways are known to coexist. As demonstrated in a study of patient tumors by Janku et al., KRAS mutations (38%) were found to coexist with mutant PIK3CA. See Janku F, et al., PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers. PLoS ONE. 2011;6(7):e22769. Thus, response to therapies targeting the PI3K pathway appears to be limited in tumors harboring KRAS mutations, even when the tumors harbor PIK3CA, PTEN, or AKT abnormalities that may predict efficacy of PI3K pathway inhibitors.

[0007] Still further, metastatic hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer is treated with endocrine therapy (ET). Unfortunately, ET resistance occurs in many cases, highlighting the need for therapies that can reverse or delay resistance. See Vernieri C et al., Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K / AKT / mTORC1 pathway with different clinical implications. Breast Cancer Res. 2020;22(1):33. In HR+ / HER2- breast cancer, aberrant signaling of the PI3K pathway to enhanced activation favors activation leading to the MAPK and estrogen receptor alpha (ERα) pathways. Specifically, ribosomal protein S6 kinase beta-1 (S6K1) and p90 ribosomal S6 kinase (RSK) synergistically regulate ERα transcription. RSK functions as a primer and S6K1 functions to maintain Ser167 phosphorylation of ERα. Thus, activation of these pathways can induce activation of ERα and induce ET resistance. See Yamnik RL et al., mTOR / S6K1 and MAPK / RSK signaling pathways coordinately regulate estrogen receptor α serine 167 phosphorylation. FEBS Letters. 2010;584(1):124-128.

[0008] In view of the above, there is a need for novel methods of treatment in patients with advanced / metastatic cancers with dysregulation of the MAPK and / or PI3K pathways, and in particular, cancers harboring NF1 aberrations (e.g., breast cancer), cancers with PTEN gene deletions or loss-of-function mutations, cancers with oncogenic KRAS mutations, and HR+ / HER2- breast cancer, including those that have progressed on endocrine therapy. Summary of the Invention

[0009] It is therefore an object of the present disclosure to provide methods of treating patients with cancers that have dysregulated MAPK and / or PI3K pathways.

[0010] It is another object of the present disclosure to provide methods of treating patients with cancer, particularly solid tumors, who harbor an NF1 abnormality (eg, a mutant NF1 gene).

[0011] It is another object of the present disclosure to provide methods of treating cancers harboring PTEN abnormalities (eg, gene defects or mutations that result in loss of function).

[0012] It is another object of the present disclosure to provide methods of treating cancers with KRAS mutations, such as the KRAS G12X mutation.

[0013] It is another object of the present disclosure to provide methods of treating HR+ / HER2- breast cancer, such as that which has progressed to at least one prior therapy (e.g., endocrine therapy, cell cycle inhibitor therapy, etc.).

[0014] These and other objects which will become apparent throughout the detailed description below have been achieved by the inventors' discovery of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (also known as "TAS0612"), or a pharma- ceutically acceptable salt thereof, which is an orally bioavailable, highly potent triple kinase inhibitor of RSK, AKT, and S6K with potential for dual inhibition of aberrant MAPK and PI3K pathways that has been found to be active in cancers such as those listed above, and which can be used to treat such cancers. Accordingly, the present disclosure provides:

[0015] (1) A method of treating a patient having a cancer, e.g., a solid tumor, with an abnormality in NF1, comprising administering to the patient an effective amount of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharma- ceutically acceptable salt thereof. This compound, having the formula below, is referred to as compound (1):

[0016] [ka]

[0017] (2) The method according to (1), wherein the solid tumor is at least one type selected from the group consisting of breast cancer, lung cancer, ovarian cancer, skin cancer, colon cancer, liver cancer, and esophageal / gastric cancer.

[0018] (3) The method of (1) or (2), wherein the solid tumor is breast cancer.

[0019] (4) The method according to (3), wherein the breast cancer is human epidermal growth factor receptor 2-negative (HER2-) breast cancer.

[0020] (5) Any one of the methods (1) to (4), wherein the patient is determined to have an abnormality in NF1 prior to the step of administering TAS0612 or a pharma- ceutically acceptable salt thereof.

[0021] (6) Any one of the methods (1) to (5), wherein the solid tumor has a concomitant abnormality in NF1 and at least one selected from the group consisting of KRAS, BRAF, PIK3CA, AKT1, and PTEN.

[0022] (7) Any one of the methods (1) to (6), wherein the solid tumor harbors an inactivating NF1 gene mutation.

[0023] (8) Any one of the methods (1) to (7), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is orally administered to a patient.

[0024] (9) Any one of the methods (1) to (8), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is administered to the patient once daily (QD).

[0025] (10) Any one of the methods (1) to (9), wherein about 10 to about 960 mg of TAS0612 or a pharma- ceutically acceptable salt thereof is administered to the patient per day.

[0026] (11) Any one of the methods (1) to (10), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is administered to the patient daily for at least 28 days.

[0027] (12) A method of treating a patient with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+ / HER2-) breast cancer, comprising administering to the patient an effective amount of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharma- ceutical acceptable salt thereof in combination with a second breast cancer therapy.

[0028] (13) The method according to (12), wherein the second breast cancer therapy is at least one selected from the group consisting of endocrine therapy, cell cycle inhibitor therapy, and radiation therapy.

[0029] (14) The method of (12) or (13), wherein the second breast cancer therapy is endocrine therapy using tamoxifen and / or fulvestrant.

[0030] (15) The method of (12) or (13), wherein the second breast cancer therapy is a cell cycle inhibitor therapy using abemaciclib, palbociclib, and / or ribociclib.

[0031] (16) The method of (12) or (13), wherein the second breast cancer therapy is radiation therapy.

[0032] (17) Any one of the methods (12) to (16), wherein the HR+ / HER2- breast cancer is recurrent or refractory HR+ / HER2- breast cancer.

[0033] (18) The method of (17), wherein the patient having recurrent or refractory HR+ / HER2- breast cancer has already received endocrine therapy and / or a therapeutic regimen using a cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor prior to the step of administering TAS0612 or a pharmacologic salt thereof.

[0034] (19) The method of (18), wherein the recurrent or refractory HR+ / HER2- breast cancer has acquired resistance or refractory to a therapeutic regimen using endocrine therapy and / or a cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor.

[0035] (20) Any one of the methods (17) to (19), wherein the recurrent or refractory HR+ / HER2- breast cancer is resistant to endocrine therapy.

[0036] (21) Any one of the methods (17) to (20), wherein the recurrent or refractory HR+ / HER2- breast cancer is resistant to tamoxifen and / or fulvestrant.

[0037] (22) Any one of the methods (17) to (21), wherein the recurrent or refractory HR+ / HER2- breast cancer is resistant to a CDK4 / 6 inhibitor.

[0038] (23) Any one of the methods (12) to (22), wherein the HR+ / HER2- breast cancer has an abnormality in NF1.

[0039] (24) Any one of the methods (12) to (23), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is orally administered to a patient.

[0040] (25) Any one of the methods (12) to (24), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is administered to a patient once daily (QD).

[0041] (26) Any one of the methods (12) to (25), wherein about 10 to about 960 mg of TAS0612 or a pharma- ceutically acceptable salt thereof is administered to the patient per day.

[0042] (27) Any one of the methods (12) to (26), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is administered to a patient daily for at least 28 days.

[0043] (28) A method of treating a patient having a cancer associated with an abnormality in PTEN, comprising administering to the patient an effective amount of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharma- ceutically acceptable salt thereof.

[0044] (29) The method according to (28), wherein the cancer is at least one type selected from the group consisting of breast cancer, thyroid cancer, renal cell carcinoma, endometrial cancer, colorectal cancer, melanoma, glioblastoma, prostate cancer, ovarian cancer, and lung cancer.

[0045] (30) The method according to (28) or (29), wherein the cancer is endometrial cancer.

[0046] (31) Any one of the methods (28) to (30), wherein the patient is determined to have an abnormality in PTEN prior to the step of administering TAS0612 or a pharma- ceutically acceptable salt thereof.

[0047] (32) Any one of the methods (28) to (31), wherein the cancer has a concurrent abnormality in PTEN and at least one selected from the group consisting of KRAS, BRAF, PIK3CA, AKT1, EGFR, HER2, TP53, NF1, and BRCA.

[0048] (33) Any one of the methods (28) to (32), wherein the cancer has simultaneous abnormalities in PTEN and PIK3CA.

[0049] (34) Any one of the methods (28) to (33), wherein the abnormality in PTEN is a mutation that results in PTEN gene deficiency or loss of function.

[0050] (35) Any one of the methods (28) to (34), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is orally administered to a patient.

[0051] (36) Any one of the methods (28) to (35), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is administered to a patient once daily (QD).

[0052] (37) Any one of the methods (28) to (36), wherein about 10 to about 960 mg of TAS0612 or a pharma- ceutically acceptable salt thereof is administered to the patient per day.

[0053] (38) Any one of the methods (28) to (37), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is administered to a patient daily for at least 28 days.

[0054] (39) A method of treating a patient with a cancer having an abnormality in KRAS, comprising administering to the patient an effective amount of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharma- ceutical acceptable salt thereof.

[0055] (40) The method according to (39), wherein the cancer is at least one type selected from the group consisting of colorectal cancer, lung cancer, pancreatic cancer, endometrial cancer, skin cancer, ovarian cancer, bile duct cancer, and breast cancer.

[0056] (41) The method of (39) or (40), wherein the patient is determined to have an abnormality in KRAS prior to the step of administering TAS0612 or a pharma- ceutically acceptable salt thereof.

[0057] (42) Any one of the methods (39) to (41), wherein the cancer has a concurrent abnormality in KRAS and at least one selected from the group consisting of BRAF, PIK3CA, PTEN, EGFR, TP53, BRCA, APC, MTOR, and SMAD4.

[0058] (43) Any one of the methods (39) to (42), wherein the cancer has a co-occurring abnormality in KRAS and at least one selected from the group consisting of PIK3CA and PTEN.

[0059] (44) Any one of the methods (39) to (43), wherein the cancer harbors a KRAS G12C mutation or a KRAS G12D mutation.

[0060] (45) The method of (44), wherein the patient is administered TAS0612 or a pharma- ceutically acceptable salt thereof in combination with a KRAS G12C-specific inhibitor or a KRAS G12D-specific inhibitor.

[0061] (46) Any one of the methods (39) to (45), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is orally administered to a patient.

[0062] (47) Any one of the methods (39) to (46), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is administered to a patient once daily (QD).

[0063] (48) Any one of the methods (39) to (47), wherein about 10 to about 960 mg of TAS0612 or a pharma- ceutically acceptable salt thereof is administered to the patient per day.

[0064] (49) Any one of the methods (39) to (48), wherein TAS0612 or a pharma- ceutically acceptable salt thereof is administered to a patient daily for at least 28 days.

[0065] (50) An antitumor agent for treating a patient having a cancer dysregulated in the MAPK and / or PI3K pathway, comprising 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharma- ceutically acceptable salt thereof.

[0066] (51) Use of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharma- ceutically acceptable salt thereof in treating patients with cancers dysregulated in the MAPK and / or PI3K pathways. (52) 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharma- ceutical acceptable salt thereof for use in treating patients with cancers dysregulated in the MAPK and / or PI3K pathways.

[0067] The preceding paragraphs have been provided by way of general introduction and are not intended to limit the scope of the claims that follow. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings, in which: [Brief description of the drawings]

[0068] [Figure 1]FIG. 1A is a diagram showing the effect of NF1 depletion by gene silencing on MAPK and PI3K signaling cascades; NF1 depletion in estrogen receptor alpha (ERα)-positive and HER2-negative breast cancer-derived MCF7 cells showed activation of both MAPK and PI3K signaling under hormone-deprived culture conditions; data are shown as immunoblots detecting NF1, pAKT, pERK, pS6, and ERα proteins in control and NF1 siRNA-transfected MCF7 cells, and FIG. 1B is a diagram showing changes in intracellular signaling upon NF1 depletion. [Diagram 2] Figures 2A-2B show the effects of compound (1), the MEK inhibitor trametinib, the PI3K inhibitor alpelisib, and the ERα-targeted degrader fulvestrant on signaling and apoptosis induction in NF1-depleted MCF7 cells (Figure 2A) and T47D cells (Figure 2B); data are shown as immunoblots detecting NF1, pPRAS40, pYB1, pS6, ERα, and cleaved PARP. [Diagram 3] FIG. 1 shows that compound (1) induces target inhibition and apoptosis in ER+ / HER2- breast cancer cell lines regardless of NF1 or estrogen status, and the effect is further enhanced when combined with fulvestrant; data are shown as immunoblots detecting NF1, pPRAS40, pYB1, pS6, ERα, and cleaved PARP. [Figure 4] 4A-4D show the effect of compound (1) on PTEN-deficient cell proliferation and apoptosis induction; FIG. 4A shows that compound (1) exhibited potent proliferation inhibition in a small cancer cell panel in which IC50 values ​​were clearly associated with PTEN gene alterations; FIG. 4B shows the results of a confirmatory large cell panel analysis; FIG. 4C shows that compound (1) induced significant apoptosis in PTEN-mutated HEC-6 cancer cells in a dose-dependent manner; FIG. 4D shows that compound (1) induced significant apoptosis in PTEN-mutated MFE-319 cancer cells in a dose-dependent manner. [Diagram 5] 5A-5B show the antitumor efficacy of compound (1) or sotorasib or the combination of compound (1) and sotorasib in nude mice bearing KRAS_G12C and PIK3CA_K111E mutant SW1573 human lung tumor xenografts as a function of tumor volume (TV) (FIG. 5A) and body weight change (BWC) (FIG. 5B); results are shown as mean ± standard error for both TV and BWC (n=5 animals / group). [Figure 6] 6A-6B show the antitumor activity of compound (1) or sotorasib or the combination of compound (1) and sotorasib in nude mice bearing KRAS_G12C mutant LU65_human lung tumor xenografts as a function of TV (FIG. 6A) and BWC (FIG. 6B); results are shown as mean ± SEM for both TV and BWC (n=5 animals / group). [Figure 7] 7A-7B show the antitumor effect of compound (1) or trametinib in nude mice bearing LS180 human colon tumor xenografts harboring KRAS_G12D, PIK3CA_H1047R, and PTEN_I67K mutations as a function of TV (FIG. 7A) and BWC (FIG. 7B); results are shown as mean ± SEM for both TV and BWC (n=5 animals / group). [Figure 8] 8A-8B show the antitumor activity of compound (1) or trametinib or the combination of compound (1) and trametinib in nude mice bearing KRAS_G12D mutant AsPC-1_human pancreatic tumor xenografts as a function of TV (FIG. 8A) and BWC (FIG. 8B); results are shown as mean ± SEM for both TV and BWC (n=5 animals / group). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0069] Compound (1) exhibited in vitro mean half-maximal inhibitory concentrations (IC) against all target kinase isoforms (RSK1, RSK2, RSK3, RSK4, AKT1, AKT2, AKT3, S6K1, and S6K2) in the range of 0.16–1.7 nmol / L. 50 Compound (1) is a novel, selective, potent and orally available multi-kinase inhibitor with MAPK and PI3K pathway activity. For this reason, compound (1) functions as a dual inhibitor of both the MAPK and PI3K pathways, providing anti-cancer effects against cancers with dysregulation in the MAPK and / or PI3K pathways, and can overcome / reverse resistance to other anti-cancer drugs, such as anti-hormones and targeted therapy agents (e.g., tyrosine kinase inhibitors). Compound (1) is described in U.S. Pat. No. 10,538,528 and its corresponding International Publication WO 2017 / 200087 (see Example 32), the contents of which are incorporated herein by reference in their entirety.

[0070] Compound (1) can be used directly (free form) or in the form of a pharmaceutically acceptable salt. The phrase "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or dosage form that is suitable for use in contact with human tissue without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts of Compound (1) are not particularly limited. Examples of such salts include base addition salts and acid addition salts. Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, perchloric acid, etc.; acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid (tosylic acid), methanesulfonic acid (mesylic acid), ethanedisulfonic acid (esylic acid), oxalic acid, These include addition salts with organic acids such as isethionic acid, formic acid, etc.; salts with alkali metals such as potassium, sodium, etc.; salts with alkaline earth metals such as calcium, magnesium, etc.; and salts with organic bases such as ammonium salts, ethylamine salts, alginate salts, organic amine salts, e.g., trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N,N'-dibenzylethylenediamine salts. Pharmaceutically acceptable salts can be synthesized by conventional chemical methods, generally by reacting compound (1) with a stoichiometric or substoichiometric amount (e.g., 0.5 equivalents) of the appropriate base or acid in water or an organic solvent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture of the two.

[0071] Compound (1) or a pharma- ceutically acceptable salt thereof may be in the form of a "solvate", which refers to a physical association of the referenced compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in an ordered and / or disordered arrangement. The solvate may contain either stoichiometric or non-stoichiometric amounts of the solvent molecules. Solvates encompass both solution-phase and isolable solvates. Exemplary solvent molecules that may form solvates include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethyl acetate, glycerin, acetone, and the like.

[0072] Compound (1) or a pharma- ceutically acceptable salt thereof may exist in amorphous or crystalline form. Compounds in single crystalline form or in mixtures of polycrystalline forms or in co-crystalline forms with other components are within the scope of the present disclosure. Crystals can be produced by application of known crystallization techniques. Preferred crystalline forms are those that have good stability, excellent oral absorption, high chemical purity, are non-hygroscopic, and are suitable for large-scale production.

[0073] Exemplary methods that can be used to synthesize compound (1) are described in U.S. Pat. No. 10,538,528 and its corresponding International Publication No. WO 2017 / 200087 (see Example 32), the contents of which are incorporated by reference in their entireties.

[0074] The terms "treat," "treating," or "treatment" of cancer in this disclosure include any effect that results in, for example, improvement of, alleviates, reduces, alters, stabilizes, improves, or eliminates a condition, disease, disorder, or the like, or improves the symptoms thereof. Specifically, these terms refer to the following: (1) stabilization, reduction (e.g., by more than 10%, 20%, 30%, 40%, 50%, preferably by 60% or more of the population of cancer cells and / or tumor size as compared to before administration), or elimination of cancer cells; (2) inhibition of cancerous cell division and / or cancerous cell proliferation; (3) reducing to some extent (or preferably eliminating) one or more symptoms associated with a pathology associated with or partially caused by uncontrolled or abnormal cell division; (4) increasing disease-free, recurrence-free, progression-free, and / or overall survival, duration, or survival rate; (5) reducing hospitalization rates; (6) reducing hospitalization duration; (7) reducing the incidence of cancer cells; (8) reducing the incidence of cancer cells; (9) reducing the incidence of cancer cells; (10) reducing the incidence of cancer cells; (11) reducing the incidence of cancer cells; (12) reducing the incidence of cancer cells; (13) reducing the incidence of cancer cells; (14) reducing the incidence of cancer cells; (15) reducing the incidence of cancer cells; (16) reducing the incidence of cancer cells; (17) reducing the incidence of cancer cells; (18) reducing the incidence of cancer cells; (19) reducing the incidence of cancer cells; (20) reducing the incidence of cancer cells; (21) reducing the incidence of cancer cells; (22) reducing the incidence of cancer cells; (23) reducing the incidence of cancer cells; (24) reducing the incidence of cancer cells; (25) reducing the incidence of cancer cells; (26) reducing the incidence of cancer cells; (27) reducing the incidence of cancer cells; (28) reducing the incidence of cancer cells; (29) reducing the incidence of cancer cells; (30) reducing the incidence of cancer cells; (31) (8) eradication, elimination, or control of primary, regional, and / or metastatic cancer; (9) stabilization or reduction in tumor or neoplasm growth (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, preferably by at least 80% compared to initial growth rate); (10) impairing tumor formation; (11) reducing mortality; (12) increasing response rate, durability of response, or number of patients in response or remission; (13) tumor size is maintained and does not increase or increases by less than 10%, preferably by less than 5%, preferably by less than 4%, preferably by less than 2%; (14) reducing the need for surgery (e.g., colectomy, mastectomy); and / or (15) preventing or reducing metastasis of cancer cells.

[0075] The cancers that can be treated herein are those that are sensitive to inhibition of the MAPK and / or PI3K pathway.In particular, the cancers that can be treated herein are those in which the Ras / Raf / MEK / ERK / RSK and / or Ras / PI3K / PTEN / AKT / mTOR / S6K cascades are abnormally activated.

[0076] Examples of types of cancer that can be treated herein include, but are not limited to, ductal tumors, carcinoid tumors, undifferentiated carcinomas, angiosarcomas, adenocarcinomas, gastrointestinal cancers (e.g., colorectal cancer ("CRC"), including colon, rectal, and appendicitis, biliary cancer, including gallbladder and bile duct cancer (cholangiocarcinoma), anal cancer, esophageal cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors ("GIST"), liver cancer, duodenal cancer, appendix cancer, and small intestine cancer), lung cancer (e.g., non-small cell lung cancer ("NSCLC"), squamous cell lung cancer, large cell lung cancer, small cell lung cancer, invasive mucinous adenocarcinoma, mesothelioma, and other lung cancers such as bronchial tumors and pleuropulmonary blastoma), urological cancers (e.g., kidney cancer, cancer), transitional cell carcinoma of the kidney ("TCC"), TCC of the renal pelvis and ureter ("PDQ"), bladder cancer, urethral cancer and prostate cancer), head and neck cancer (e.g., eye cancer, retinoblastoma, intraocular melanoma, hypopharyngeal cancer, pharyngeal cancer, laryngeal cancer, laryngeal papilloma, metastatic cervical squamous cell carcinoma of unknown primary, paranasal and sinonasal squamous cell carcinoma (SNSCC), oral (mouth) cancercancer), lip, throat, oropharyngeal, olfactory neuroblastoma, nasal and paranasal sinus, nasopharyngeal, and salivary gland cancers), endocrine cancers (e.g., thyroid cancer, parathyroid cancer, multiple endocrine neoplasia syndrome, thymoma and thymic carcinoma, pancreatic cancer, including pancreatic ductal adenocarcinoma ("PDAC"), pancreatic neuroendocrine tumors, and islet cell tumors), breast cancer (ductal carcinoma in situ ("DDAC"), cancers of the male and female reproductive tract (e.g., cervical cancer, ovarian cancer, endometrial cancer, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, gestational trophoblastic neoplasia (GTD), extragonadal germ cell tumors, extracranial germ cell tumors, germ cell tumors, testicular cancer, and penile cancer); cancers of the brain and nervous system (e.g., astrocytoma, brain stem glioma, brain tumor, glioblastoma (G) BM), craniopharyngioma, central nervous system ("CNS") cancer, chordoma, ependymoma, embryonal tumor, neuroblastoma, paraganglioma, atypical teratotumor, oligodendroglioma, oligoastrocytoma, oligodendroglioma, anaplastic oligoastrocytoma, ganglioglioma, central neurocytoma, medulloblastoma, germinoma, meningioma, schwannoma, GH-secreting pituitary adenoma, PRL-secreting pituitary adenoma, ACTH-secreting pituitary adenoma, nonfunctioning pituitary adenoma, hemangioblastoma, and epidermoid tumor), skin cancer (e.g. These include solid tumors such as basal cell carcinoma ("BCC"), squamous cell skin cancer ("SCC"), Merkel cell carcinoma, and melanoma), tissue and bone cancers (e.g., soft tissue sarcoma, rhabdomyosarcoma, fibrous histiocytoma of bone, Ewing's sarcoma, malignant fibrous histiocytoma of bone ("MFH"), osteosarcoma, and chondrosarcoma), cardiovascular cancers (e.g., cardiac cancer and tumors), appendix cancer, pediatric and adolescent cancers (e.g., pediatric adrenocortical carcinoma, midline tract carcinoma, hepatocellular carcinoma ("HCC"), hepatoblastoma, and Wilms' tumor), and virus-induced cancers (e.g., HHV-8-associated cancer (Kaposi's sarcoma) and HIV / AIDS-associated cancers).

[0077] Cancers that are also suitable for treatment include, but are not limited to, hematological and plasma cell malignancies (e.g., cancers affecting the blood, bone marrow and / or lymph nodes), such as multiple myeloma, leukemia and lymphoma, myelodysplastic syndromes and myeloproliferative disorders. Leukemias include, but are not limited to, acute lymphoblastic leukemia ("ALL"), acute myelogenous (myeloid) leukemia ("AML"), chronic lymphocytic leukemia ("CLL"), chronic myelogenous leukemia ("CML"), acute monocytic leukemia ("AMoL"), hairy cell leukemia, and / or other leukemias. Lymphomas include, but are not limited to, Hodgkin's lymphoma and non-Hodgkin's lymphoma ("NHL"). In some embodiments, the NHL is a B-cell lymphoma and / or a T-cell lymphoma. In some embodiments, NHL includes, but is not limited to, diffuse large B-cell lymphoma ("DLBCL"), small lymphocytic lymphoma ("SLL"), chronic lymphocytic leukemia ("CLL"), mantle cell lymphoma ("MCL"), Burkitt's lymphoma, cutaneous T-cell lymphomas including mycosis fungoides and Sézary syndrome, AIDS-related lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia ("WM")), primary central nervous system (CNS) lymphoma, central nervous system malignant lymphoma, and / or other lymphomas.

[0078] The therapeutic methods of the present disclosure are particularly useful in the treatment of solid tumors / cancers such as lung cancer (e.g., non-small cell lung cancer ("NSCLC"), invasive mucinous adenocarcinoma, etc.), breast cancer (e.g., ductal carcinoma in situ ("DCIS"), lobular carcinoma in situ ("LCIS"), etc.), male and female reproductive cancers (e.g., endometrial / uterine cancer, ovarian cancer, etc.), urinary cancer (e.g., prostate cancer, etc.), gastrointestinal cancer (e.g., colon / colorectal cancer, appendicitis, etc.), endocrine cancer (e.g., pancreatic cancer, etc.), and skin cancer (e.g., melanoma).

[0079] The methods disclosed herein can also be used as tumor-agnostic treatments for malignancies that are sensitive to inhibition of the MAPK and / or PI3K pathways.

[0080] While cancers of various stages and resectability may respond to the disclosed treatments, the methods herein may be particularly useful in treating advanced (stage III) and metastatic (stage IV) disease, "recurrent" and "refractory" cancers - cancers that have previously failed to respond to medical treatment. "Recurrent" cancers are cancers that have recurred (returned) after a period during which the cancer was usually undetectable. The cancer may return in the same location as the original (primary) tumor or in another location in the body. "Refractory" cancers may appear as resistant / refractory from the onset or from the acquisition of resistance / refractory properties by cancer cells during the course of previous therapies, and thus may include recurrent cancers that initially respond to treatment but often return in a more aggressive / resistant form. Recurrent or refractory cancers may be either resectable or unresectable.

[0081] Cancers responsive to the treatments disclosed herein may, in some cases, harbor abnormalities in one or more cancer driver genes / components associated with the MAPK and / or PI3K pathways (e.g., NF1, PTEN, PIK3CA, KRAS, etc.) that result in or contribute to cancer formation and / or development.

[0082] "Cancer driver genes" are genes that, when genetically altered, confer a growth advantage to cells and aid in tumor growth. Cancer driver genes generally fall into two classes: tumor suppressor genes and oncogenes. "Tumor suppressor genes", or tumor suppressor genes, negatively regulate cell growth. Loss of function of the proteins encoded by these genes, through gene deletion, mutation, or inactivation, relieves cells from growth constraints and contributes to malignant transformation. "Oncogenes" result in activated forms or overexpression levels of proteins that normally help cells grow and, when genetically altered, allow cells to survive and grow rather than destined for apoptosis. Thus, the gain of function of oncogenes combined with the loss of function of tumor suppressor genes determine the processes that control tumor formation and growth.

[0083] In this disclosure, gene / protein "abnormalities" include protein overexpression, gene amplification (e.g., copy number changes), gene / protein mutations (e.g., insertion, substitution, or deletion mutations including those classified as nonsense, missense, splicing, or frameshift mutations), chromosomal translocations / insertions / inversions, gene rearrangements or gene fusions (a subset of gene rearrangements), promoter hypermethylation, post-translational modifications, and the like, including combinations thereof, that contribute to cancer formation and / or development.

[0084] The cancer to be treated herein, for example, solid tumor, can have NF1 abnormality.NF1 is a tumor suppressor gene that encodes neurofibromin protein, which functions as a suppressor of RAS-GTP activation, and NF1 deficiency leads to RAS activation and downstream MAPK pathway activation.The preferred cancer to have NF1 abnormality is solid tumor.

[0085] The abnormality in NF1 can be in the form of one or more inactivating mutations, including but not limited to nonsense, frameshift, missense, splicing, or deletion mutations. Inactivating mutations can be germline mutations, known to increase the risk of breast cancer in women under the age of 50 and which may result in increased cancer-related deaths, or somatic mutations, which are rare in the primary cancer but are associated with poor prognosis and increased risk of recurrence. Madanikia SA, et al., Increased risk of breast cancer in women with NF1. Am J Med Genet A 2012;158A:3056-60;Uusitalo E, et al., Distinctive cancer associations in patients with neurofibromatosis type 1. J Clin Oncol 2016; 34:1978-86;Sharif S, et al., Women with neurofibromatosis 1 are at a See moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet 2007; 44:481-4; and Griffith OL, et al., The prognostic effects of somatic mutations in ER-positive breast cancer. Nat Commun 2018; 9:3476.

[0086] A preferred embodiment of the present disclosure includes treating patients with solid tumors, particularly breast cancer, such as advanced / metastatic HER2- breast cancer, that carry one or more NF1 gene mutations. "HER2-" means that the HER2 expression level is considered to be within the normal range, for example, compared to healthy cells. Such HER2- breast cancers include ER / PR(+), HER2- breast cancer, and triple-negative breast cancer (TNBC).

[0087] NF1 gene variants, also referred to as NF1 mutations, include, but are not limited to, R1204W, X465_splice, S2751Rfs * 27?, I679Dfs * 21. T467Hfs * 3. P678Rfs * 10, P388T, Y628Tfs * 3, V2205A, N2341Tfs * 5. Q1336 * , and N184Wfs *17. Other examples of NF1 gene mutations include, but are not limited to, Q83Ter, R192Ter, R304Ter, P504fs, G629R, T770fs, Q948Ter, c.3198-1G>C, S1078Ter, A1098fs, S1329Ter, K1429Ter, Q1515K, K1752N, c.5268+1G>T, S2435del, and G2683A. See Pearson, A., et al., Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance. Clin Cancer Res, 2020; (26)(3), 608-622. Unless otherwise specified, any reference to NF1 amino acid sequence information is based on human wild-type NF1 isoform 1, accessible from the National Center for Biotechnology Information (NCBI) protein database under accession number NP_001035957, etc. Isoforms of NF1 are also known by those of skill in the art, and the present disclosure also encompasses those isoforms. With respect to the alterations (e.g., mutations) in NF1 discussed herein, it should be understood that the alterations in the isoform may be at a different position than that specified for NF1 due to deletion or insertion of amino acids in the isoform, but that the alterations in the isoform nevertheless correspond to the positions specified on NF1.

[0088] In addition to breast cancer, other specific examples of cancer types with NF1 aberrations that can be treated herein include, but are not limited to, lung cancer (e.g., NSCLC), ovarian cancer, cancers of the brain and nervous system, skin cancer (e.g., melanoma), and gastrointestinal cancers such as colon cancer, liver cancer, and esophageal gastric cancer.

[0089] Cancers harboring NF1 abnormalities may, in some cases, also have co-occurring abnormalities associated with one or more other cancer driver genes, such as, but not limited to, the MAPK and / or PI3K pathways, including Ras (e.g., HRAS, KRAS, NRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF) (e.g., G464V and / or V600E, etc.), PIK3CA, AKT1 (e.g., E17K and / or L52R, etc.), PTEN, estrogen receptor 1 (ESR1), and tumor protein p53 gene (TP53).

[0090] With respect to PIK3CA abnormality, one or more PIK3CA gene variants are specifically mentioned, which can be interchangeably referred to as PIK3CA mutations, examples of which include, but are not limited to, K111E, E542X, including E542K / A / G / Q / D, E545X, including E545K / A / G / Q / D, L866F, K567R, and H1047X, including H1047R / L / Y / Q. Unless otherwise specified, any reference to PIK3CA amino acid sequence information is based on human wild-type PIK3CA isoform alpha, which can be accessed from the National Center for Biotechnology Information (NCBI) protein database under accession number NP_006209.2, etc. Isoforms of PIK3CA are also known by those skilled in the art, and the present disclosure also encompasses these isoforms. It should be understood that the changes in an isoform may be at a different position than that specified for PIK3CA due to deletion or insertion of amino acids in the isoform, but nevertheless are changes that correspond to the positions specified on PIK3CA.

[0091] The cancers treated herein include those with PTEN abnormalities. PTEN encodes a ubiquitously expressed phosphatase that opposes the PI3K / AKT / mTOR cascade. PTEN loss of function can cause a spectrum of phenotypes, including benign hyperproliferation, malignant tumors, and metabolic and neurodevelopmental disorders. Germline PTEN abnormalities are associated with an increased lifetime risk of breast cancer (estimated lifetime risk of 85%), thyroid cancer (35%), renal cell carcinoma (34%), endometrial cancer (28%), colorectal cancer (9%), and melanoma (6%). See Tan MH, et al., Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400-407. In addition, individuals with germline PTEN mutations have a seven-fold increased risk of developing a second primary malignant neoplasm compared to the general population in the United States.

[0092] Abnormalities in PTEN that result in loss of function / PTEN insufficiency can be in the form of one or more inactivating mutations, including but not limited to nonsense, frameshift, missense, and deletion mutations, chromosomal deletions, promoter hypermethylation, and post-translational modifications.Cancers with PTEN abnormalities can express truncated proteins, full-length proteins, or complete protein defects, which can be caused by germline or somatic mutations.

[0093] These can be interchangeably referred to as PTEN mutations. Examples of mutations that result in PTEN gene deficiency or loss of function include, but are not limited to, I67K, K267Rfs, and the like. * 9 / * / fs * Including K267X, R234Afs * 1, L247 * , C71Y, L112P, C124S, R130Q / G / L / P / * / fs *Including R130X, C136Y, Y155C, Q214 * , R233 * , Q245 * , E299 * , T319 * / fs * Including T319X, N323fs * and R335 * See Sun, Y., et al. PTENα functions as an immune suppressor and promotes immune resistance in PTEN-mutant cancer. Nat Commun 12, 5147 (2021). Unless otherwise specified, any reference to PTEN amino acid sequence information is based on the human wild-type PTEN isoform, accessible from the National Center for Biotechnology Information (NCBI) protein database under accession number NP_000305.3, etc. Isoforms of PTEN are also known by those skilled in the art, and the present disclosure also encompasses these isoforms. It should be understood that the changes in the isoforms may be at positions different from those specified on PTEN due to deletion or insertion of amino acids in the isoform, but nevertheless, the changes in the isoforms are changes corresponding to the positions specified on PTEN.

[0094] A preferred embodiment of the present disclosure includes treating patients with advanced / metastatic cancer, particularly solid tumors, with one or more PTEN abnormalities, such as PTEN gene deletions or mutations resulting in loss of function. Specific examples of such types of cancer include, but are not limited to, breast cancer, thyroid cancer, renal cell carcinoma, endometrial cancer, colon / appendiculoma, melanoma, glioblastoma (brain tumor), prostate cancer, ovarian cancer, and lung cancer.

[0095] In addition to PTEN abnormalities, cancers may also, in some cases, have co-occurring abnormalities associated with one or more other cancer driver genes, such as, but not limited to, Ras (e.g., HRAS, KRAS, NRAS), (BRAF) (e.g., G464V and / or V600E, etc.), PIK3CA (e.g., previously described mutants), AKT1 (e.g., E17K and / or L52R, etc.), epidermal growth factor receptor (EGFR), HER2, TP53, NF1, and breast cancer gene (BRCA). In particular, cancers carrying co-occurring abnormalities in both PTEN and PIK3CA have been identified as being highly sensitive to compound (1), and therefore, these cancers represent preferred targets for treatment herein.

[0096] The cancers treated herein may carry KRAS abnormalities, particularly KRAS mutations. KRAS is a proto-oncogene located at a critical signaling junction between extracellular growth receptors and growth-promoting pathways that, when mutated, overactivates numerous downstream effector pathways, such as the MAPK and / or PI3K signaling pathways. KRAS is one of the most frequently mutated genes in cancer, with the highest frequency in colorectal adenocarcinoma, lung adenocarcinoma, multiple myeloma, and pancreatic adenocarcinoma. The genetic interactions of oncogenic KRAS mutations are allele- and tissue-specific, which results in inconsistent therapeutic responses and clinical outcomes. See Cook, JH et al., The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat Commun 12, 1808 (2021). The gain-of-function KRAS abnormality may be a germline mutation or a somatic mutation.

[0097] KRAS abnormalities may occur, for example, at codons 12, 13, 61, and 146, with specific reference to activating mutations (e.g., missense) at codon 12. KRAS gene variants that can be referred to interchangeably as KRAS mutations include, but are not limited to, one or more point mutations such as G12X (wherein X is, for example, A, C, D, R, S, or V), G13X (wherein X is, for example, A, C, D, R, S, or V), Q61X (wherein X is, for example, E, H, K, L, P, and R), and A146X (wherein X is, for example, E, G, P, S, T, and V). In particular, the cancer treated herein is KRAS G12X mutant cancer, preferably KRAS G12C mutant cancer or KRAS G12D mutant cancer. Unless otherwise specified, any reference to KRAS amino acid sequence information is based on human wild-type KRAS isoform a, which is accessible from the National Center for Biotechnology Information (NCBI) protein database under accession number NP_001356715.1, etc. Isoforms of KRAS are also known by those skilled in the art, and the present disclosure also encompasses these isoforms. With respect to the changes (e.g., mutations) in KRAS discussed herein, it should be understood that the changes in the isoform may be at a different position from the position specified on KRAS due to deletion or insertion of amino acids in the isoform, but the changes in the isoform nevertheless correspond to the positions specified on KRAS.

[0098] A preferred embodiment of the present disclosure includes treating patients with advanced / metastatic cancer, particularly solid tumors, with KRAS G12C mutation. Another preferred embodiment of the present disclosure includes treating patients with advanced / metastatic cancer, particularly solid tumors, with KRAS G12D mutation. Specific examples of cancer types that are known to have such mutational characteristics and are candidates for treatment herein include, but are not limited to, colon cancer, lung cancer (e.g., NSCLC), pancreatic cancer, endometrial cancer, skin cancer, ovarian cancer, bile duct cancer, and breast cancer.

[0099] In addition to KRAS abnormalities, cancers may also, in some cases, have co-occurring abnormalities associated with one or more other cancer driver genes, such as, but not limited to, BRAF (e.g., G464V and / or V600E), PIK3CA (e.g., those previously described), PTEN (e.g., those previously described), AKT1 (e.g., E17K and / or L52R, etc.), EGFR, TP53, BRCA, adenomatous polyposis coli (APC), target of rapamycin (MTOR), and mothers against decapentaplegic homolog 4 (SMAD4). In particular, KRAS mutant cancers (e.g., G12C or G12D mutants) with co-occurring abnormalities in PIK3CA, PTEN, or both PIK3CA and PTEN have been found to be highly sensitive to compound (1), and therefore these cancers represent preferred targets for treatment herein.

[0100] Patients with cancers that carry KRAS abnormalities can be treated with compound (1) or a pharma- ceutically acceptable salt thereof as monotherapy. Alternatively, patients with cancers that carry KRAS abnormalities can be treated with compound (1) or a pharma- ceutically acceptable salt thereof in combination with KRAS mutant-specific inhibitors. KRAS mutant-specific inhibitors include inhibitors that target and bind to specific KRAS mutant proteins, or other downstream pathway inhibitors that are active against specific oncogenic KRAS mutant cancers (i.e., those that prevent or attenuate the action of specific KRAS mutant proteins without specifically binding to KRAS proteins). Such combination therapy is intended to cover both combination therapy administered simultaneously and combination therapy administered sequentially (as pre- or post-treatment).

[0101] For example, cancer carrying KRAS G12C mutation can be treated with compound (1) or its pharmaceutically acceptable salt in combination with KRAS G12C specific inhibitor. Examples of KRAS G12C specific inhibitor include, but are not limited to, AMG510 (sotorasib), MRTX849 (adagrasib), ARS-1620, ARS-853, JNJ-74699157 (ARS-3248), LY3499446, GDC-6036, D-1553, JDQ433, JAB-21822, and RM-007.

[0102] In another example, cancer carrying KRAS G12D mutation can be treated with compound (1) or its pharma- ceutical acceptable salt in combination with KRAS G12D specific inhibitor. Examples of KRAS G12D specific inhibitor include, but are not limited to, MRTX1133 and KRpep-2d.

[0103] The cancer to be treated herein may be hormone receptor positive (HR+) breast cancer, preferably HR+ and HER2- breast cancer. By "HR+" is meant cancer in which estrogen receptor, most notably ERα, is present / detectable, thereby allowing the cancer to use estrogen to grow (ER+), cancer in which progesterone receptor is present / detectable, thereby allowing the cancer to use progesterone to grow (PR+), or cancer that is both ER+ and PR+.

[0104] Patients with HR+ / HER2- breast cancer can be treated with compound (1), or a pharma- ceutically acceptable salt thereof, as monotherapy.

[0105] Alternatively, patients with HR+ / HER2- breast cancer can be treated with compound (1) or a pharma- ceutically acceptable salt thereof in combination with a second breast cancer therapy. Here, compound (1) or a pharma- ceutically acceptable salt thereof can be considered as a "first breast cancer therapy," while a breast cancer therapy that is not based on the administration of compound (1) is referred to as a "second breast cancer therapy." The second breast cancer therapy can include the administration of one or more anticancer agents (examples of which are described herein below) (other than compound (1) or a salt thereof) and / or non-pharmaceutical therapy, such as radiation therapy. Such combination therapy is intended to cover both combination therapy administered simultaneously and combination therapy administered sequentially (as pre- or post-treatment).

[0106] With regard to anti-cancer agents administered as second line breast cancer therapy for the treatment of HR+ / HER2- breast cancer, endocrine therapy (ET) and / or cell cycle inhibitor therapy are particularly preferred.

[0107] Endocrine therapy includes, but is not limited to, treatment with one or more of aromatase inhibitors (e.g., anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole), selective estrogen receptor modulators (e.g., tamoxifen, 4-hydroxytamoxifen, acolbifene, EM-800, toremifene, droloxifene, LY117018, raloxifene, nafoxidine, and trioxyphene), and selective estrogen receptor degraders (e.g., fulvestrant, brilanestrant, elacestrant).

[0108] Cell cycle inhibitor therapy includes, but is not limited to, treatment with one or more cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitors, such as abemaciclib, palbociclib, and ribociclib.

[0109] Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of compound (1) in this combination therapy can be determined as described herein. Radiation therapy can be administered through one of several methods or a combination of methods, including, but not limited to, external beam radiation therapy, internal beam radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. The term "brachytherapy" as used herein refers to radiation therapy delivered by spatially restricted radioactive material inserted in the body or near the site of a tumor or other proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable radiation sources for use as cell regulators of the present disclosure include both solid and liquid sources. As non-limiting examples, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclide that emits photons, beta particles, gamma rays, or other therapeutic radiation. The radioactive material can also be a fluid made from any solution of a radionuclide, for example, a solution of I-125 or I-131, or the radioactive fluid can be made using a slurry of a suitable fluid containing small particles of a solid radionuclide, such as Au-198, Y-90, etc. Additionally, the radionuclide can be embodied in a gel or radioactive microspheres.

[0110] The HR+ breast cancer may be recurrent or refractory HR+ breast cancer, preferably recurrent or refractory HR+ / HER2- breast cancer.

[0111] Patients with recurrent or refractory cancer (e.g., breast cancer) who have previously undergone at least one treatment regimen with one or more anticancer drugs, preferably at least two treatment regimens with at least two different anticancer drugs, can be treated with compound (1) or a pharma- ceutically acceptable salt thereof. In some cases, recurrent or refractory cancer may have acquired resistance to or refractoriness from previous treatment regimens. For example, patients with HR+ cancer who have previously been treated with one or more anticancer drugs (e.g., endocrine therapy and / or cell cycle inhibitors) and have progressed, failed to respond to, or relapsed from previous treatment with anticancer drugs may develop resistance / refractoryness as a result of exposure of the cancer to anticancer drugs.

[0112] A preferred embodiment of the present disclosure includes administering compound (1) or a pharmacologic acceptable salt thereof to a patient with recurrent or refractory HR+ breast cancer, preferably HR+ / HER2- breast cancer, where the patient has previously undergone at least one treatment with endocrine therapy (ET) and one or more of cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitors, and optionally has acquired resistance thereto or refractory therefrom.For example, the cancer may be endocrine therapy-resistant breast cancer, such as aromatase inhibitor-resistant cancer, selective estrogen receptor modulator-resistant cancer, or selective estrogen receptor degrader-resistant cancer, with specific reference to tamoxifen-resistant breast cancer, fulvestrant-resistant breast cancer, and the like.In another example, the cancer includes CDK4 / 6 inhibitor-resistant cancer, such as abemaciclib-resistant cancer, palbociclib-resistant cancer, ribociclib-resistant cancer, and the like.

[0113] Resistance / refractory from previous treatment with ET can optionally manifest in cancer in the form of ER downregulation; ligand-binding-independent ER activation, e.g., via estrogen receptor mutations (e.g., ESR1 mutations); downregulation of ER corepressors, such as via NF1 gene mutants; bypass signaling via the Ras pathway; dysregulated MAPK pathway and / or PI3K pathway signaling, e.g., from genetic abnormalities in one or more components of these pathways, such as upregulation of RSK, AKT, and / or S6K; or any other cancer driver genetic abnormality resulting in loss of function of tumor suppressor genes / proteins or gain-of-function changes in oncogenes / oncogene-encoded proteins. Resistance / refractory from previous treatment with one or more CDK4 / 6 inhibitors can optionally be manifested in cancer in the form of retinoblastoma (RB) gene / protein defects, known resistance factors for tumor suppressors and resistance to CDK4 / 6 inhibitors; PTEN gene defects or mutations resulting in loss of function; ESR1 mutations; NF1 gene mutations; dysregulated MAPK and / or PI3K pathway signaling pathways; or any other cancer driver gene abnormality resulting in loss of function of tumor suppressor genes / proteins or gain of function changes in oncogenes / oncogene-encoded proteins. In particular, recurrent or refractory HR+ breast cancer can carry NF1 gene mutations. When treating recurrent or refractory HR+ breast cancer with combination therapy, compound (1) can be administered to restore / sensitize resistance to the co-administered anticancer agent.

[0114] Compound (1), or a pharma- ceutically acceptable salt thereof, can also be used to treat estrogen-refractory breast cancers, such as those that are estrogen hypersensitive or have acquired resistance through estrogen-independent activation of the estrogen receptor.

[0115] Before starting treatment, it can be determined whether the patient has progressed or relapsed from a previous therapy (e.g., has a recurrent or refractory cancer that has been previously treated with endocrine therapy (ET), CDK4 / 6 inhibitors, etc.) and / or has one or more abnormalities as identified above (e.g., NF1, PTEN, KRAS, etc.). Thus, the method can include a pre-screening step to determine whether the patient meets at least one of these criteria and is a good candidate for treatment. Such a determination can be made from analyzing a family history of cancer including abnormalities, by genotyping the patient or analyzing any biological sample from the patient, including blood or tumor samples taken from the patient using assays such as those described herein below, or from medical records or previous tests performed on the patient. If the patient is determined to have a recurrent or refractory cancer, such as recurrent or refractory HR+ / HER2- breast cancer, and / or carries one or more genetic abnormalities such as those described in this disclosure, treatment with compound (1) or a pharmacologic acceptable salt thereof is appropriate.

[0116] Predictive biomarkers that can be used to identify individuals likely to be responsive to the treatment herein include, but are not limited to, NF1 gene variants, PTEN deficiency or loss-of-function mutations, and KRAS mutations (specifically KRAS G12X mutations). Companion diagnostic (CDx) tests can be developed to analyze biological samples.

[0117] The receptor status and genotype of a patient, including whether or not they carry any gene / protein abnormality, can be determined from previous tests performed on the patient, for example, during pre-screening of the patient, through fresh biopsy, or can be determined otherwise according to known assays, including approved or approved in vitro diagnostic (IVD) assays or assays for this purpose. Examples include, but are not limited to, next generation sequencing (NGS)-based gene panels, whole exome profiling, polymerase chain reaction (PCR), in situ hybridization (ISH), including fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), flow cytometry, or other assays that can determine receptor status or abnormality on tumor tissue or circulating tumor DNA (ctDNA), RNA, protein, etc. For example, a biopsy can be performed on a patient who does not have a stored tumor tissue sample, and the fresh tumor biopsy can be analyzed to confirm existing abnormalities.

[0118] The terms "administer", "administering", "administration" and the like refer to methods that can be used to enable delivery of an active ingredient to the site where a biological effect is desired. The routes or modes of administration are as set forth herein. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical / transdermal, and rectal / vaginal administration. Those skilled in the art are familiar with the available administration techniques. Oral administration is preferred.

[0119] In this disclosure, the term "administration schedule" refers to a plan showing the type, amount, duration, procedure, etc. of drugs during drug treatment in a chronological order, including the dosage of each drug, the method of administration, the order of administration, and the date of administration. The date designated for administration is determined before the start of drug administration. Administration is continued by repeating the course that includes the set of administration schedule as a "treatment course."

[0120] With respect to the dosing schedules of the present disclosure, "continuous" means daily administration without interruption during the course of treatment. If the dosing schedule follows an "intermittent" dosing schedule, days of administration may be followed by "rest days" or days during which the drug is not administered.

[0121] A "drug holiday" refers to when a drug is not administered during a predetermined dosing schedule. For example, after undergoing several courses of treatment, a patient may be assigned regular drug holidays as part of a dosing schedule, for example, before resuming active treatment again.

[0122] The dosage and duration of treatment depend on factors such as drug bioavailability, mode of administration, drug toxicity, sex, age, lifestyle, body weight, use of other drugs and dietary supplements, disease stage, body tolerance and resistance to the administered drug, etc., and are determined and adjusted accordingly. The appropriate dosage may vary from individual to individual. The appropriate dosage in any individual case can be determined using techniques such as dose escalation.

[0123] A patient may receive, for example, from about 1 mg / day, to about 5 mg / day, to about 10 mg / day, to about 15 mg / day, to about 20 mg / day, to about 30 mg / day, to about 40 mg / day, to about 50 mg / day, to about 60 mg / day, to about 77 mg / day, to about 80 mg / day, to about 100 mg / day, to about 120 mg / day, to about 160 mg / day, up to about 1,500 mg / day, up to about 1,200 mg / day, up to about 960 mg / day, up to about 800 mg / day, The compound (1) or a pharmacologic acceptable salt thereof can be used for treatment with a dosage level for continuous (administration 7 days per week) dosing of up to about 640 mg / day, up to about 500 mg / day, up to about 400 mg / day, up to about 320 mg / day, up to about 300 mg / day, up to about 280 mg / day, up to about 250 mg / day, up to about 240 mg / day, up to about 200 mg / day, up to about 180 mg / day. Dosage levels can vary within the range of about 20 mg / day to about 960 mg / day, about 40 mg / day to about 640 mg / day, and about 80 mg to about 320 mg / day, etc. The dosage level can be changed during the dosing schedule, for example, dosing can be initiated using a low dosage for a period of time and then increased, or dosing can be initiated using a high dosage for a period of time and then decreased.

[0124] A patient can be treated with Compound (1) or a pharma- ceutically acceptable salt thereof at a dose level for intermittent dosing of, for example, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 200 mg / day, about 300 mg / day, about 400 mg / day, about 500 mg / day, about 600 mg / day, up to about 3,000 mg / day, up to about 2,500 mg / day, up to about 2,000 mg / day, up to about 1,500 mg / day, up to about 1,000 mg / day, up to about 900 mg / day, up to about 800 mg / day, up to about 700 mg / day, or any dose level within the range.

[0125] Dosing can be continuous (administration 7 days per week) or intermittent, depending, for example, on the pharmacokinetics of the drug and the clearance / accumulation of a particular patient. If intermittent, the schedule can be, for example, 4 days on and 3 days off (rest days) per week, or any other intermittent dosing schedule deemed appropriate using sound medical judgment. Continuous dosing is preferred. Dosing can be once per day (QD) or more than once per day (bid, tid, etc.), with a dose of about 20-960 mg / day QD being preferred. The daily dose can be administered as a single dose or multiple separate divided doses. For example, two tablets, each containing 40 mg of Compound (1) or a pharma- ceutically acceptable salt thereof, can be administered to a patient once per day (QD) for a total dose of 80 mg / day. In another example, two tablets, each containing 40 mg of Compound (1) or a pharma- ceutically acceptable salt thereof, can be administered to a patient twice daily (bid) for a total dose of 160 mg / day.

[0126] Regardless of whether it is continuous or intermittent, the administration continues for a certain treatment cycle, typically a cycle of at least 28 days, and this cycle can be repeated with or without a drug holiday. Longer or shorter cycles, such as 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 ​​days, or any range therebetween, can also be used. The cycle can be repeated without or with a drug holiday, depending on the patient. Other schedules are possible, depending on the presence or absence of adverse events, the response of the cancer to the treatment, the convenience of the patient, etc. "Adverse event" refers to any undesirable or unintended disease or its symptoms that occurs in a patient to whom a drug is administered. It does not matter whether there is a causal relationship with the drug. For intermittent dosing, dosing can occur, for example, on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27; days 1, 4, 8, 11, 15, 19, 23, and 27; days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 of a 28 day cycle.

[0127] Such continuous or intermittent administration is also applicable to combination therapy in which compound (1) or a pharma- ceutically acceptable salt thereof is administered in combination with one or more other anti-cancer agents or non-pharmaceutical therapies.

[0128] Compound (1) can be administered using an up-titration regimen, whereby the patient is started at a low dose over a period of time (e.g., 2 weeks), followed by an up-titration of the dose. The dose can be titrated until either the target or maximum dose is reached, or the patient experiences an adverse event, at which point the up-titration is stopped and drug dosing is reduced to a previous dose where the adverse event was not experienced or was not severe enough to require treatment to be stopped. Patients experiencing adverse events can also be managed with dose interruptions (e.g., drug holidays) if deemed appropriate. Exemplary dosing for a continuous regimen is provided above, although higher or lower doses can be used depending on the patient's response to treatment and the presence or absence of adverse events. If the dose is well tolerated, the dose can be increased. Administration can be continued for one cycle, e.g., 28 days, followed by repeating the cycle if desired.

[0129] As mentioned above, compound (1) or its pharmaceutically acceptable salts can be specially formulated for administration in solid or liquid form, including those suitable for: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets or capsules, e.g., buccal, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous or epidural injection, e.g., as a sterile solution or suspension, or sustained release formulation; (3) topical / transdermal administration, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin; (4) vaginally or rectally, e.g., as a pessary, cream or foam; or (5) intranasally. In the case of compound (1) or its pharmaceutically acceptable salts, oral formulations are preferred.

[0130] The formulation can be prepared using a pharma- ceutically acceptable carrier, etc., by using a known formulation method. A pharma- ceutically acceptable carrier is a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate, or stearic acid, or a solvent encapsulating material, that is involved in the transport or transportation of the target compound from one organ or part of the body to another organ or part of the body. Each carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharma- ceutically acceptable carriers include, to name a few, (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) maltitol, ... (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; ( (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic compatible substances utilized in pharmaceutical formulations, such as cyclodextrins, liposome, and micelle forming agents, such as bile acids.

[0131] Pharmaceutically acceptable carriers can be classified into various general-purpose agents such as excipients, binders, disintegrants, lubricants, diluents, solubilizing agents, suspending agents, swelling agents, isotonicity agents, pH adjusting agents, buffers, stabilizers, colorants, flavorings, taste masking agents, and the like.

[0132] Examples of excipients include, but are not limited to, lactose, sucrose, D-mannitol, glucose, starch (corn starch), calcium carbonate, kaolin, microcrystalline cellulose, fumaric acid, and anhydrous silicic acid.

[0133] Examples of binders include, but are not limited to, water, ethanol, 1-propanol, 2-propanol, simple syrup, liquid glucose, liquid a starch, liquid gelatin, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose (e.g., low viscosity hydroxypropylcellulose), hydroxypropylmethylcellulose (hypromellose), hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone.

[0134] Examples of disintegrants include, but are not limited to, low-substituted hydroxypropyl cellulose, dry starch, partially pregelatinized starch, microcrystalline cellulose, carmellose sodium, carmellose calcium, D-mannitol, crospovidone, croscarmellose sodium, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, and lactose.

[0135] Examples of lubricants include, but are not limited to, hydrogenated oils, sucrose fatty acid esters, sodium lauryl sulfate, stearic acid, purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.

[0136] Examples of coloring agents include, but are not limited to, FD&C Yellow No. 5, FD&C Blue No. 2, food lake color, iron sesquioxide, yellow sesquioxide, and titanium dioxide.

[0137] Examples of sweeteners / flavoring agents include, but are not limited to, aspartame, saccharin (as sodium, potassium or calcium saccharin), cyclamate (as the sodium, potassium or calcium salts), sucralose, acesulfame K, thaumatin, neohesperidin, dihydrochalcone, ammoniated glycyrrhizin, dextrose, maltodextrin, fructose, levulose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, oil of wintergreen, peppermint oil, spearmint oil, sassafras oil, clove oil, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, lemon, lime, and lemon lime.

[0138] If desired, oral preparations can be provided with an enteric coating or a coating to increase the duration of action by any desired method. Examples of such coatings include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyethylene glycol, and Tween 80®.

[0139] Compound (1) or a pharma- ceutically acceptable salt thereof is preferably formulated in a solid dosage form for oral administration, such as in the form of capsules, tablets, pills, sugar-coated tablets, powders, granules, lozenges, and the like, with film-coated tablets being preferred. Compound (1) or a pharma- ceutically acceptable salt thereof may be mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose (e.g., lactose monohydrate), sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption enhancers, such as For example, quaternary ammonium compounds and surfactants such as poloxamers and sodium lauryl sulfate; (7) wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants (e.g., fatty acid esters of sorbitan and polyalkoxylated fatty acid esters of sorbitan, e.g., Tween 80®); (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate (e.g., vegetable derived), solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) colorants; and (11) controlled release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the formulations can also include pH adjusting or buffering agents. Solid compositions of similar types can also be utilized as fillers in soft and hard shell gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0140] Tablets can be produced by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared with binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active or dispersing agents. Molded tablets can be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets, and other solid dosage forms, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. An example of a coating formulation can include hypromellose, polyethylene glycol, titanium dioxide, and optionally colorants. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, with hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres in various proportions to provide the desired release profile. They can be formulated for immediate release, for example, lyophilized. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents into the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use.These preparations can also optionally contain opacifying agents, and can be of a composition that releases active ingredient only or preferentially in a certain part of the digestive tract, optionally in a delayed form.Examples of embedding compositions that can be used include polymeric substances and waxes.Active ingredient can also be in microencapsulated form, with one or more of the above-mentioned excipients if appropriate.

[0141] Coated tablet dosage forms of Compound (1) or a pharma- ceutically acceptable salt thereof are preferred, such as those containing fumaric acid, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol, and titanium dioxide as inactive ingredients.

[0142] Compound (1) or a pharma- ceutically acceptable salt thereof can be formulated for parenteral administration, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion administration, by combining Compound (1) or a pharma- ceutically acceptable salt thereof with one or more pharma- ceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents, or sterile powders that can be reconstituted into a sterile injectable solution or dispersion immediately before use. Examples of suitable aqueous and non-aqueous carriers that can be used include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifiers, dispersing agents, pH adjusting agents, stabilizers, local anesthetics, etc. Prevention of the action of microorganisms on the subject compounds can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the compositions. In addition, prolonged absorption of injectable pharmaceutical forms can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0143] The therapeutic method of the present disclosure can include administration of compound (1) or a pharma- ceutically acceptable salt thereof as a monotherapy. Treatment can also include administration as adjuvant chemotherapy after surgical removal of a tumor to prevent tumor recurrence, as well as neoadjuvant chemotherapy prior to surgery to surgically remove a tumor. In some cases, such as with breast cancer, surgery can include lumpectomy, mastectomy, breast reconstruction, and the like. In some cases, such as with lung cancer, surgery can include pneumonectomy, lobectomy, wedge resection, tube resection, thoracoscopy, and the like. Treatment can also include administration of compound (1) or a pharma- ceutically acceptable salt thereof during or after radiation therapy, or as an adjuvant therapy to prevent tumor recurrence in patients where other treatments, such as surgery, have rendered the patient cancer-free.

[0144] Patients may be treated herein who have not previously undergone a therapeutic regimen using an anti-cancer agent, i.e., compound (1) or a pharmaceutically acceptable salt thereof is administered as first-line chemotherapy. Alternatively, as previously described, patients may be treated who have previously undergone a therapeutic regimen using one or more anti-cancer agents (other than compound (1) or a salt form thereof), including, but not limited to, endocrine therapy and CDK4 / 6 inhibitors. That is, compound (1) or a pharmaceutically acceptable salt thereof may be administered as second, third, fourth line therapy, etc.

[0145] Examples of anti-cancer drugs include, but are not limited to, chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormonal and anti-hormonal agents, targeted therapy agents, and anti-angiogenic agents.Many anti-cancer drugs can be classified into one or more of these groups.Although some anti-cancer drugs have been classified into specific groups or subgroups herein, many of these drugs can also be listed into one or more other groups or subgroups, as would be currently understood in the art. The anti-cancer drug is not particularly limited, and examples thereof include, but are not limited to, chemotherapeutic agents, mitotic inhibitors, plant alkaloids, alkylating agents, antimetabolites, platinum analogs, enzymes, topoisomerase inhibitors, retinoids, aziridines, antibiotics, hormones, antihormones, antiestrogens, antiandrogens, antiadrenal, androgens, targeted therapies, immunotherapeutics, biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, anti-PD-1 agents, anti-PD-L1 agents, anti-TIGIT agents, colony stimulating factors, immunomodulators, immunomodulatory imide (IMiD), anti-CTLA4 agents, anti-LAGl agents, anti-OX40 agents, GITR agonists, CAR-T cells, BiTEs, sig These include neurotransmitter inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, HER2 inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell cycle inhibitors, anti-angiogenic agents, matrix metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, HIF-1α inhibitors, HIF-2α inhibitors, fibroblast growth factor (FGF) inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, BRAF inhibitors, RAS inhibitors, gene expression regulators, autophagy inhibitors, apoptosis inducers, anti-proliferative agents, and glycolysis inhibitors.

[0146] Non-limiting examples of chemotherapeutic agents include antimitotics and plant alkaloids, alkylating agents, antimetabolites, platinum analogues, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.

[0147] Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes, such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel; demecolcine; epothilones; eribulin; etoposide (VP-16); etoposide phosphate; navelbine; noscapine; teniposide; saliblastine; vinblastine; vincristine; vindesine; vinflunine; and vinorelbine.

[0148] Non-limiting examples of alkylating agents include nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, cytophosphan, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembicine, phenesterine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, romosulfan, bromobutane ... These include methylamelamines such as altretamine, nimustine, ranimustine, streptozotocin, and TA-07; ethyleneimines and methylamelamines such as altretamine, thiotepa, triethylenemelamine, triethylenethiophosphoramide, triethylenephosphoramide, and trimethylolmelamine; ambamustine; bendamustine; dacarbazine; cyclophosphamide; etoglucide; irofulven; mafosfamide; mitobronitol; mitolactol; pipobroman; procarbazine; temozolomide; treosulfan; and triaziquone.

[0149] Non-limiting examples of antimetabolites include folic acid analogs, such as aminopterin, denopterin, edatrexate, methotrexate, pteropterin, raltitrexed, and trimetrexate; purine analogs, such as 6-mercaptoproprine, 6-thioguanine, fludarabine, forodesine, thiamiprine, and thioguanine; pyrimidine analogs, such as 5-fluorouracil (5-FU), tegafur / gimeracil / oteracil potassium, tegafur / uracil, trifluridine, trifluridine / tipiracil hydrochloride, 6-azaurate ... These include lysine, ancitabine, azacitidine, capecitabine, carmofur, cytarabine, decitabine, dideoxyuridine, doxifluridine, doxifluridine, enocitabine, floxuridine, galocitabine, gemcitabine, and sapacitabine; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; broxuridine; cladribine; cyclophosphamide; cytarabine; emitefur; hydroxyurea; mercaptopurine; nelarabine; pemetrexed; pentostatin; tegafur; and troxacitabine.

[0150] Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

[0151] Non-limiting examples of enzymes include asparaginase and pegaspargase.

[0152] Non-limiting examples of topoisomerase inhibitors include acridine carboxamides, amonafide, amsacrine, belotecan, elliptinium acetate, exatecan, indolocarbazole, irinotecan, lutotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.

[0153] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin.

[0154] Non-limiting examples of aziridines include benzodopa, carboquone, metuledopa, and uredopa.

[0155] Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracycline antibiotics such as aclarubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, nogalamycin, pirarubicin, and valrubicin; 6-diazo-5-oxo-L-norleucine; aclacinomycin; actinomycin; ausramycin; azaserine; bleomycin; cactinomycin; calicheamicin; carubicin; carminomycin; carcino These include: filin; chromomycin; dactinomycin; detorubicin; esorubicin; esperamicin; geldanamycin; marcelomycin; mitomycin; mitomycin C; mycophenolic acid; olivomycin; novantrone; peplomycin; porfiromycin; porfiromycin; puromycin; queramycin; rebeccamycin; rodorubicin; streptonigrin; streptozotocin; tanespimycin; tubercidin; ubenimex; zinostatin; zinostatin stimalamer; and zorubicin.

[0156] Non-limiting examples of hormonal and antihormonal agents include antiandrogens, such as abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide; antiestrogens, such as 4-hydroxytamoxifen, aromatase-inhibiting 4(5)-imidazole, EM-800, fosfestrol, fulvestrant, keoxifene, LY117018, onapristone, raloxifene, tamoxifen, toremifene, and trioxifene; antiadrenal, such as aminoglutethimide, dexaminoglutethimide, mitoxantrone, and tertazepam; androgens such as calcitonin, drostanolone propionate, epithiostanol, mepitiostane, and testolactone; abarelix; anastrozole; cetrorelix; deslorelin; exemestane; fadrozole; finasteride; formestane; histrelin (RL0903); human chorionic gonadotropin; lanreotide; LDI200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; nafoxidine; osaterone; prednisone; thyrotropin alfa; and triptorelin.

[0157] Non-limiting examples of immunotherapeutic agents (ie, immunotherapies) include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony stimulating factors, and immunomodulatory agents.

[0158] Non-limiting examples of biological response modifiers, including cytokine inhibitors (cytokines) such as interferons and interleukins, include interferon alfa / alpha, e.g., interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon alfacon-1, pegylated interferon alpha-2a, pegylated interferon alpha-2b, and leukocyte alpha interferon; interferon beta, e.g., interferon beta-1a, and interferon beta-1b; interferon gamma, e.g., natural interferon gamma-1a, and interferon gamma-1b; aldesleukin; interleukin-1 beta; interleukin-2; oprelvekin; sonermin; tasonermin; and virulisin.

[0159] Non-limiting examples of tumor vaccines include APC8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin 17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma cancer lysate vaccine (New York Medical College), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), TICE® BCG (Bacille Calmette-Guerin), and viral melanoma cell lysate vaccine (Royal Newcastle Hospital).

[0160] Non-limiting examples of monoclonal antibodies include abagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), daclizumab, daratumumab, denosumab, edrecolomab, gemtuzumab ozogamicin, HER-2 and Fc MAb (Medarex), ibritumomab tiuxetan, idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), ipilimumab, lintuzumab, LYM-1-iodine 131 MAb (Techni clone), mitumomab, moxetumomab, ofatumumab, polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), ranibizumab, rituximab, veltuzumab, and trastuzumab.

[0161] Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies, such as cemiplimab, zimblerimab, nivolumab, and pembrolizumab; anti-PD-L1 agents or antibodies, such as atezolizumab, avelumab, and durvalumab; anti-TIGIT agents or antibodies, such as tiragolumab and domvanalimab; anti-CTLA-4 agents or antibodies, such as ipilimumab and tremelimumab; anti-LAG1 agents; and anti-OX40 agents.

[0162] Non-limiting examples of colony stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte-macrophage colony stimulating factor, lenograstim, religistim, millimostim, molgramostim, nartograstim, pegfilgrastim, and sargramostim.

[0163] Non-limiting examples of additional immunotherapeutic agents include BiTEs, CAR-T cells, GITR agonists, imiquimod, immunomodulatory imides (IMiDs), mismatched double-stranded RNA (Ampligen), resiquimod, SRL172, and thymalfasin.

[0164] Targeted therapeutic agents include, for example, monoclonal antibodies and small molecule drugs.Non-limiting examples of targeted therapeutic agents include signal transduction inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, HER2 inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell cycle inhibitors, angiogenesis inhibitors, matrix metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factor (FGF) inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, BRAF inhibitors, RAS inhibitors, heat shock protein (HSP) 90 inhibitors, gene expression regulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.

[0165] Non-limiting examples of signal transduction inhibitors include tyrosine kinase inhibitors, multi-targeted kinase inhibitors (i.e., other than compound (1) or a salt thereof), anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, lonidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR and / or HER2 inhibitors.

[0166] Non-limiting examples of EGFR inhibitors include small molecule antagonists of EGFR, such as afatinib, brigutinib, erlotinib, gefitinib, lapatinib, neratinib, dacomitinib, vandetanib, and osimertinib; as well as antibody-based EGFR inhibitors, including any anti-EGFR antibody or antibody fragment capable of partially or completely blocking EGFR activation by its natural ligand. Antibody-based EGFR inhibitors include, for example, those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al, 1995, Clin. Cancer Res. 1: 1311-1318; Huang, SM, et al., 1999, Cancer Res. 15:59(8): 1935-40; and Yang, X., et al., 1999, Cancer Res. 59: 1236-1243; the monoclonal antibody Mab E7.6.3 (Yang, 1999 supra); Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof; specific antisense nucleotides or siRNA; afatinib, cetuximab; matuzumab; necitumumab; nimotuzumab; panitumumab; and zalutumumab.

[0167] Non-limiting examples of HER2 inhibitors include HER2 tyrosine kinase inhibitors, such as afatinib, lapatinib, neratinib, and tucatinib; and anti-HER2 antibodies or drug conjugates thereof, such as trastuzumab, trastuzumab emtansine (T-DM1), pertuzumab, margetuximab, trastuzumab deruxtecan (DS-8201a), and trastuzumab duocarmazine. Non-limiting examples of FGFR inhibitors (FGFR-TKIs) include anlotinib, ponatinib, dovitinib, lucitanib, lenvatinib, nintedanib, erdafitinib (JNJ-42756493), infigratinib (BGJ398), pemigatinib (INCB054828), rogaratinib (BAY1163877), derazantinib (ARQ087), futibatinib (TAS-120), LY2874455, AZD4547, Debio1347, and fisogatinib (BLU-554).

[0168] Non-limiting examples of histone deacetylase (HDAC) inhibitors include belinostat, panobinostat, romidepsin, and vorinostat.

[0169] Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.

[0170] Non-limiting examples of cell cycle inhibitors, including CDK inhibitors, include abemaciclib, alvocidib, palbociclib, and ribociclib.

[0171] Non-limiting examples of anti-angiogenic agents (or angiogenesis inhibitors) include, but are not limited to, matrix metalloproteinase (MMP) inhibitors; VEGF inhibitors; EGFR inhibitors; TOR inhibitors, such as everolimus and temsirolimus; PDGFR kinase inhibitors, such as crenolanib; HIF-lα inhibitors, such as PX478; HIF-2α inhibitors, such as velzutifan and the HIF-2α inhibitors described in WO 2015 / 035223; fibroblast growth factor (FGF) or FGFR inhibitors, such as B-FGF and RG13577; hepatocyte growth factor inhibitors; KDR inhibitors; anti-Ang1 and anti-Ang2 agents; anti-Tie2 kinase inhibitors; Tek antagonists (U.S. Pat. App. Pub. No. 2013 / 0233634; No. 6,413,932); anti-TWEAK agents (U.S. Pat. No. 6,727,225); ADAM disintegrin domains for antagonizing binding of integrins to their ligands (U.S. Pat. App. Pub. No. 2002 / 0042368); anti-eph receptor and / or anti-ephrin antibodies or antigen binding regions (U.S. Pat. Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; and 6,057,124); and anti-PDGF-BB antagonists and antibodies or antigen binding regions that specifically bind to PDGF-BB ligands.

[0172] Non-limiting examples of matrix metalloproteinase (MMP) inhibitors include MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, prinomastat, RO32-3555, and RS13-0830. Examples of useful matrix metalloproteinase inhibitors are described, for example, in WO 96 / 33172, WO 96 / 27583, EP 1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 0606046, EP 093178, and WO 093178. No. 8, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO 1999 / 007675, EP 1786785, EP 1181017, U.S. Patent Application Publication No. 2009 / 0012085, U.S. Patent Nos. 5,863,949, 5,861,510, and EP 0780386. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and / or MMP-9 compared to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

[0173] Non-limiting examples of VEGF and VEGFR inhibitors include bevacizumab, cediranib, CEP7055, CP547632, KRN633, orantinib, pazopanib, pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAP™.

[0174] Other antiangiogenic agents include, but are not limited to, 2-methoxyestradiol, AE941, alemtuzumab, alpha-D148Mab (Amgen, US), alphastatin, anecortave acetate, angiocidin, angiogenesis inhibitors (SUGEN, US), angiostatin, anti-Vn Mab (Crucell, Netherlands), atiprimod, axitinib, AZD9935, BAY RES2690 (Bayer, Germany), BC1 (Genova Cancer Institute, Italy), beloranib, benefin (Lane Labs, US), cabozantinib, CDP791 (Celltech Group, UK), chondroitinase AC, cilengitide, combrestatin A4 prodrug, CP564959 (OSI, US), CV247, CYC381 (Harvard University, US), E7820, EHT0101, endostatin, enzastaurin hydrochloride, ER-68203-00 (IVAX, US), fibrinogen E fragment, Flk-1 (ImClone Systems, US), form of FLT1 (VEGFR1), FR-111142, GCS-100, GW2286 (GlaxoSmithKline, UK), IL-8, ilomastat, IM-862, irsogladine, KM-2550 (Kyowa Hakko, Japan), lenalidomide, lenvatinib, MAb alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, US), MAbVEGF (Xenova, UK), marimastat, maspin (Sosei, Japan), metastatin, motuporamine C, M-PGA, ombrabulin, OXI4503, PI88, platelet factor 4, PPI2458, ramucirumab, rBPI21 and BPI-derived antiangiogenic agents (XOMA, US), regorafenib, SC-236, SD-7784 (Pfizer, US), SDX103 (University of California, San Diego, US), SG292 (Telios, US), SU-0879 (Pfizer, US), TAN-1120, TB C-1635, tecevatinib, tetrathiomolybdate, thalidomide, thrombospondin 1 inhibitors, Tie-2 ligand (Regeneron, US), tissue factor pathway inhibitor (EntreMed, US), tumor necrosis factor alpha inhibitors, tumstatin, TZ93, urokinase-type plasminogen activator inhibitors, vadimezan, vandetanib, vasostatin, vatalanib, VE-cadherin-2 antagonists, xanthrizol, XL784 (Exelixis, US), dib-aflibercept, and ZD6126.

[0175] Anticancer drugs that can be combined with compound (1) can also be active agents that disrupt or inhibit RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways, or are PD-1 and / or PD-L1 antagonists. Examples include, but are not limited to, RAF inhibitors, EGFR inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, or immunotherapies, including monoclonal antibodies, immunomodulatory imids (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGl, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.

[0176] Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib.

[0177] Non-limiting examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib.

[0178] Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, ravoxertinib, ulixertinib, and ASTX029.

[0179] Non-limiting examples of PI3K inhibitors include 17-hydroxywortmannin analogs (e.g., WO 06 / 044453); AEZS-136; alpelisib; AS-252424; buparlisib; CAL263; copanlisib; CUDC-907; dactolisib (WO 06 / 122806); demethoxyviridin; duvelisib; GNE-477; GSK1059615; IC87114; idelalisib; INK 1117; LY294002; palomid 529; paxalisib; perifosine; PI-103; PI-103 hydrochloride; pictilisib (e.g., WO 09 / 036,082; WO 09 / 055,730); PIK90; PWT33597; SF1126; sonolisib; TGI00-115; TGX-221; XL147; XL-765; wortmannin; taselisib (GDC-0032); and ZSTK474.

[0180] Non-limiting examples of AKT inhibitors include Akt-1-1 (inhibits Aktl) (Barnett et al., (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (Barnett et al., (2005) Biochem. J. 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al., (2004) Br. J. Cancer 91, 1808-12); lH-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05011700); indole-3-carbonyl and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) J Nutr. 134(12 Suppl), 3493S-3498S); perifosine (Dasmahapatra et al., (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); triciribine (Yang et al., (2004) Cancer Res. 64, 4394-9;imidazooxazone compounds including trans-3-amino-1-methyl-3-[4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl]-cyclobutanol hydrochloride (WO 2012 / 137870);afuresertib;capivasertib;8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2 , 4-triazolo[3,4-f][1,6]naphthyridin-3(2H)-one (MK2206) and its pharmaceutically acceptable salts; AZD5363; trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol (TAS-117) and its pharmaceutically acceptable salts; and ipatasertib.

[0181] Non-limiting examples of TOR inhibitors include deforolimus; ATP-competitive TORC1 / TORC2 inhibitors, including PI-103, PP242, PP30, and torin1; TOR inhibitors of FKBP12 enhancers, including temsirolimus, everolimus, rapamycin and its derivatives, WO 9409010; rapalogs, e.g., those described in WO 98 / 02441 and WO 01 / 14387. As disclosed in the International Publication No. 2003 / 013366, for example, AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin; 40-epi-(tetrazolyl)-rapamycin (also known as ABT578); AZD8055; 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapamycin, and the International Publication No. 2003 / 0133666. Other derivatives disclosed in WO 05 / 005434; U.S. Pat. No. 5,258,389, WO 94 / 090101, WO 92 / 05179, U.S. Pat. Nos. 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, WO 93 / 111130, WO 94 / 0 Nos. 2136, 94 / 02485, 95 / 14023, 94 / 02136, 95 / 16691, 96 / 41807, 96 / 41807 and U.S. Pat. No. 5,256,790; and phosphorus-containing rapamycin derivatives (e.g., WO 05 / 016252).

[0182] Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.

[0183] Non-limiting examples of SHP2 inhibitors include JAB-3068, RMC-4630, TNO155, SHP-099, RMC-4550, and the SHP2 inhibitors described in WO 2019 / 167000, WO 2020 / 022323, and WO 2021 / 033153.

[0184] Non-limiting examples of RAS inhibitors include AMG510 (sotrasib), MRTX849 (adagrasib), LY3499446, JNJ-74699157 (ARS-3248), ARS-1620, ARS-853, GDC-6036, D-1553, JDQ433, JAB-21822, RM-007, RM-008, MRTX1133, and KRpep-2d. Non-limiting examples of HSP90 inhibitors include pimitespib.

[0185] Additional non-limiting examples of anti-cancer drugs that may be suitable for use include, but are not limited to, 2-ethylhydrazide, 2,2',2"-trichlorotriethylamine, ABVD, aceglatone, acemannan, aldophosphamide glycoside, alpharadin, amifostine, aminolevulinic acid, anagrelide, ANCER, ancestim, anti-CD22 immunotoxin, antitumor herbs, apaziquone, aruglavin, arsenic trioxide, azathioprine, BAM002 (Novelos), bcl-2 (Genta), bestravsil, biricoder, bisan Tren, bromocriptine, brostallicin, bryostatin, buthionine sulfoximine, calyculin, cell cycle non-specific antineoplastic agents, cermoleukin, clodronate, clotrimazole, cytarabine ocfosfate, DA3030 (Dong-A), defofamine, denileukin diftitox, dexrazoxane, diaziquone, dichloroacetic acid, dilazep, discodermolide, docosanol, doxercalciferol, edelfosine, eflornithine, EL532 (Elan), elfomitin, elsamitrucin, eniluracil, etanilin. Folic acid supplements such as Dazol, Exisulind, Ferruginol, Folinic acid, Gacytosine, Gallium nitrate, Gimeracil / Oteracil / Tegafur combination (S-1), Glycopin, Histamine dihydrochloride, HIT diclofenac, HLA-B7 gene therapy (Vical), Human fetal alpha-fetoprotein, Ibandronate, Ibandronic acid, ICE chemotherapy regimen, Imexon, Iobenguane, IT-101 (CRLX101), Lanikidar, LC9018 (Yakult), Leflunomide, Lentinan, Levamisole + Fluorouracil, Lovastatin, Lucantone, Masoprocol, Melarsoprol, Metoclopramide, Miltefosine, Miproxifen, Mitoguazone, Mitozolomide, Mopidamol, Motexafine Gadolinium, MX6 (Galderma), Naloxone + Pentazocine, Nitracrine, Nolatrexed, NSC631570 Octreotide (Ukrain), Olaparib, P-30 protein, PAC-1, Palifermin, Pamidronate, Pamidronic acid, Pentosan polysulfate sodium, Fenamet, Picibanil, Pixantrone, Platinum, Podophyllinic acid,These include porfimer sodium, PSK (polysaccharide K), rabbit antithymocyte polyclonal antibody, rasburiembodiment, retinoic acid, rhenium Re186 etidronate, romurtide, samarium (Sm) lexidronam, sizofiran, sodium phenylacetate, sparfosic acid, spirogermanium, strontium-89 chloride, suramin, swainsonine, talaporfin, tariquidar, tazarotene, tegafur-uracil, temoporfin, tenuazonic acid, tetrachlorodecaoxide, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, TLC ELL-12, tositumomab-iodine 131, trifluridine-tipiracil combination, troponin I (Harvard University, US), urethane, valspodar, verteporfin, zoledronic acid, and zosuquidar. ,

[0186] As used in this disclosure, the terms "combination", "combined" or variations thereof are intended to define a therapy that includes the use of a combination of two or more compounds / drugs. The terms can refer to compounds / drugs that are administered as part of the same overall administration schedule. The individual dosages of the two or more compounds / drugs can be different. Combination therapy is intended to encompass administration of the compounds / drugs in a sequential manner, i.e., administration where each compound / drug is administered at different times (e.g., the first drug is administered as pre-treatment or post-treatment with respect to the second drug of the combination), as well as administration of the compounds / drugs, or at least two of the compounds / drugs, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the patient a single dosage form having a fixed ratio of each compound / drug, or multiple single dosage forms for each of the compounds / drugs. Sequential or substantially simultaneous administration of each compound / drug can be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue (e.g., buccal). Compounds / drugs can be administered by the same route or by different routes.For example, the first compound / drug of the selected combination can be administered by intravenous infusion, while the other compound / drug of the combination can be administered orally.Alternatively, for example, all compounds / drugs can be administered orally, or all compounds / drugs can be administered by intravenous infusion.

[0187] Combination therapy can also include the administration of the compound / drug as described above, further combined with other biologically active ingredients and non-drug therapy (e.g., surgery or radiation therapy).When combination therapy further includes non-drug therapy, the non-drug therapy can be carried out at any suitable time, as long as the beneficial effect from the joint action of the combination of compound / drug and non-drug therapy is achieved.For example, when appropriate, the beneficial effect is still achieved when non-drug therapy is temporarily removed from the administration of compound / drug, perhaps for several days or even weeks. EXAMPLES

[0188] [Example 1] Evaluating the effect of NF1 depletion on the MAPK and PI3K pathways in ER+ / HER2- breast cancer cells To examine the effect of NF1 depletion on cell proliferation signals in ER+ / HER2- breast cancer cells, NF1 siRNA was transfected into human ER+ / HER2- breast cancer-derived MCF7 cells, and changes in the phosphorylation status of molecules representative markers of MAPK and PI3K signaling activity were confirmed by immunoblotting. MCF7 cells cultured in phenol red-free RPMI1640 medium containing 10% charcoal-stripped FBS were transfected with NF1 siRNA to a final concentration of 10 μmol / L using Lipofectamine RNAiMAX. The cells were then incubated at 37°C, 5% CO2 for 1 day. E2 (estrogen) was then added to the medium at a final concentration of 1 nmol / L and the cells were cultured for 3 days, after which the cells were harvested and cell extracts were prepared. The expression of the following protein molecules was compared between NF1 knockdown cells and control cells by immunoblotting: (1) NF1 to confirm NF1 knockdown, (2) pAKT Ser473, pERK Thr202 / Tyr204, and pS6RP Ser235 / 236 to monitor changes in MAPK and PI3K signaling activity, and (3) ERα to monitor cellular responsiveness to estrogen stimulation. As shown in Figure 1A, the phosphorylation levels of pAKT, pERK, and pS6 were increased in NF1 knockdown cells compared to control MCF7 cells. These results indicate the simultaneous enhancement of MAPK and PI3K signaling due to NF1 downregulation or dysfunction due to NF1 gene alteration. In addition, ERα expression was also decreased, suggesting that sensitivity to ER-targeting drugs may be reduced. These findings suggest that ER-targeting drugs are less effective in NF1-deficient ER+ / HER2- breast cancer cells and that inhibition of MAPK and PI3K signaling pathways is more effective.

[0189] [Example 2] Evaluation of the growth inhibitory effect of compound (1) in NF1-depleted ER+ / HER2- breast cancer cells To examine the growth inhibitory effect of compound (1) on NF1-depleted ER+ / HER2- breast cancer cells MCF7 and T47D, serial dilutions of compound (1) were exposed to the cells for 3 days as in the previous experiments. Growth inhibition curves in MCF7 and T47D cells were obtained and the half-maximal inhibitory concentrations (IC50) of growth inhibition were calculated as shown in Table 1.

[0190] [Table 1] As a result, compound (1) showed relatively strong IC50 values ​​in NF1 knockdown MCF7 and T47D cells, even in the presence or absence of estrogen. These results suggest that compound (1) may have a significant growth inhibitory effect on breast tumors with NF1 abnormalities.

[0191] [Example 3] Evaluation of the growth inhibitory effect of compound (1) in NF1 mutant cell lines NF1 gene alterations have been reported not only in ER+ / HER2- breast cancer, but also in other breast cancer subtypes, such as HER2+ and triple-negative breast cancer. They have also been found in colorectal cancer, melanoma, and lung cancer, and NF1 abnormalities may be responsible for the deregulated proliferation potential of some cancers. To investigate the growth inhibitory effect of compound (1) in NF1 mutant cancer cell lines, IC50 values ​​of growth inhibition assays were obtained and then compared in Table 2.

[0192] [Table 2] In this experiment, to compare the growth inhibitory effect of compound (1) with that of MAPK and PI3K signaling inhibitors, the IC50 values ​​of trametinib (as a MEK inhibitor) and alpelisib (as a PI3K inhibitor) were obtained and compared. Several NF1 mutant cell lines were found to be insensitive to MEK and / or PI3K inhibitors, with IC50 values ​​ranging from 16 to over 10,000 nmol / L for trametinib and 179 to over 10,000 nmol / L for alpelisib, whereas the IC50 values ​​for compound (1) were less than 1 μmol / L, except for MDA-MB-231 cells, indicating that compound (1) is more potent against NF1 mutant cell proliferation than drugs that inhibit either signaling pathway alone.

[0193] [Example 4] Evaluation of target inhibition and apoptosis induction by compound (1) in NF1-depleted ER+ / HER2+ breast cancer cell lines To investigate the mechanism of action of compound 1 in inhibiting the proliferation of NF1 knockdown breast cancer cells, compound 1, trametinib, alpelisib, and fulvestrant were exposed to NF1 knockdown MCF7 and T47D cells at the indicated final concentrations for 24 h. NF1, pPRAS40 Thr246, pYB1 Ser102, pS6RP Ser235 / 236, ERα, and cleaved PARP were detected by immunoblotting. PRAS40, YB1, and S6RP are specific phosphorylation substrates for AKT, p90RSK, and p70S6K kinases, respectively, and reduction in these phosphorylation signals indicates target inhibition by compound (1) has occurred. As shown in Figures 2A-2B, compound (1) reduced pPRAS40, pYB1, and pS6RP signaling in a concentration-dependent manner in both cells. These target inhibitions were also observed in NF1 knockdown cells, indicating that compound (1) is effective even in cells with NF1 aberrantly activated MAPK and PI3K signaling, as described in Figure 1A. The cleaved PARP signal serves as a marker for detecting apoptosis induction. In MCF7 cells, alpelisib induced apoptosis in control cells (non-targeting siRNA) even as a single agent, but the induction of apoptosis is found to be attenuated in NF1 knockdown cells. Compound (1) single-agent treatment also induced apoptosis in MCF7 control cells (non-targeting siRNA cells), but in contrast to alpelisib, compound (1) did not show attenuation of apoptosis induction in NF1 knockdown cells. Furthermore, in T47D cells, the effect of inducing apoptosis by compound (I) was observed at a significantly higher level in NF1 knockdown cells than in control cells (non-targeting siRNA cells). Such a significantly higher level of apoptosis induction effect in NF1 knockdown cells compared to control cells was not observed in the alpelisib treatment group. These findings indicate that compound (1) has promising pharmacological effects for antitumor activity against NF1-deficient breast cancer cells.

[0194] [Example 5] Evaluation of the antitumor activity of compound (1) in combination with fulvestrant in the presence and absence of estrogen and NF1 The actual standard of care for ER+ / HER2- breast cancer is with adjuvant therapy such as tamoxifen, letrozole, or fulvestrant. Patients with recurrent or refractory tumors are treated with the additional use of CDK4 / 6 inhibitors or alpelisib for PIK3CA mutant cancers. As shown in Figure 3, we evaluated whether the antitumor effect of compound (1) can be enhanced by combination with fulvestrant in two types of conditions that promote cancerous growth: (1) the presence and absence of estrogen treatment, and (2) NF1 as wild-type condition and siRNA-targeted NF1 knockdown condition. Apoptosis induction by compound (1) was observed in both NF1 wild-type and NF1 knockdown cells in the presence or absence of estrogen treatment. Treatment with fulvestrant alone clearly demonstrated ER reduction, but all fulvestrant treatment groups had little apoptosis-inducing activity. However, in combination with compound (1) and fulvestrant, apoptosis induction was significantly enhanced in the presence of estrogen treatment in NF1 knockdown cells compared to cells treated with fulvestrant alone. These results suggest that compound (1) may be used in combination with fulvestrant for inhibiting the proliferation of ER+ / HER2- breast cancer cells.

[0195] [Example 6] Investigation of genetic factors associated with susceptibility using cell panels Cell proliferation inhibition assays were performed according to standard protocols for 72 hours using the CellTiter Glo 2.0 assay. Compound (1) showed strong growth inhibition in cancer cell lines derived from various human cancer origins (Figure 4A). The low IC50 value of compound (1) indicates a remarkable potency in inhibiting the growth of resistant cells harboring oncogenic genetic alterations, such as driver gene mutations (KRAS, EGFR, ERBB2, and PIK3CA) and / or tumor suppressor gene defects (PTEN and TP53). Among these genetic alterations, cells with genetic variants of the PTEN gene appeared to correlate with the strong IC50 value of compound (1). To confirm the correlation between the IC50 of compound (1) and PTEN genetic alterations, a large-scale cell panel analysis was performed. In Figure 4B, a correlation between sensitivity to compound (1) and PTEN genetic alterations was clearly observed. For further confirmation of the sensitivity of cells with PTEN alterations to compound (1), dose-dependent apoptosis induction was assessed by monitoring the levels of cleaved caspase-3 and cleaved PARP using PTEN mutant HEC-6 and MFE-319 cells treated for 48 hours after the addition of serially diluted compound (1) (Figures 4C-4D). Treatment of both cell lines with compound (1) increased cleaved caspase-3 and cleaved PARP in a concentration-dependent manner compared to controls. These results suggest that compound (1) induces apoptosis in PTEN mutant human cancer cells through inhibition of the target kinase.

[0196] [Example 7] Evaluation of the antitumor activity of compound (1) or sotorasib or the combination of compound (1) and sotorasib in nude mice bearing KRAS_G12C and PIK3CA_K111E mutant SW1573 human lung tumor xenografts The lung cancer-derived SW1573 cell line harbors a KRAS G12C mutation but has been reported to have low sensitivity to the G12C inhibitor sotorasib (also known as AMG510) (see also Example 11 below). To evaluate the antitumor activity of compound (1) against SW1573 tumors implanted subcutaneously in nude mice, a comparison of the efficacy of compound (1) with AMG510 alone and the synergistic efficacy of AMG510 + compound (1) was performed. Dosing solutions containing Compound (1) were prepared using 0.5% w / v hydroxypropylmethylcellulose (HPMC) with added hydrochloric acid to achieve a final concentration of 0.1N. 30 mg / kg and 60 mg / kg Compound (1) for monotherapy were prepared and administered PO QD for 14 days. The antitumor activity of AMG510 was also evaluated at 30 mg / kg with 0.5% w / v HPMC by PO QD for 14 days. Combination treatment with 60 mg / kg Compound (1) and 30 mg / kg AMG510 by daily oral gavage for 14 days. At the 15th day evaluation, all groups treated with compound (1) showed significant tumor growth inhibition compared to the control group (P<0.01 for 30 mg / kg and P<0.001 for 60 mg / kg, Dunnett's test). The 30 mg / kg AMG510 treatment group also showed significant tumor growth inhibition at approximately the same level as 30 mg / kg compound (1). The combination group using compound (1) and AMG510 showed significant tumor growth inhibition (P<0.001, Dunnett's test). The results are summarized in Figures 5A-5B and Table 3.

[0197] [Table 3] The T / C ratios of 30, 60mg / kg compound (1), 30mg / kg AMG510, and the combination of compound (1) and AMG510 were 55%, 38%, 54%, and 20%, respectively. Except for a case of accidental death due to a dosing error in the combination treatment group, no mouse had a weight loss of more than 20% from day 0 throughout the experiment. These results demonstrated that compound (1) showed efficacy at the same or better level than that of AMG510 in KRAS G12C mutant cells that also carry a PIK3CA mutation. In addition, the combination of compound (1) and AMG510 also demonstrated a clear enhancement of antitumor efficacy over each agent alone, with acceptable tolerability.

[0198] [Example 8] Evaluation of the antitumor activity of compound (1) or sotorasib or the combination of compound (1) and sotorasib in nude mice bearing KRAS_G12C mutant LU65_human lung tumor xenografts To investigate the antitumor efficacy of compound (1) against KRAS G12C mutant LU65 human lung tumors, compound (1) at 80 mg / kg / day, AMG510 at 30 mg / kg / day, and their combinations were administered to male BALB / c nude mice subcutaneously implanted with LU65 tumor xenografts. Compound (1) and AMG510 alone and their combinations were administered daily by oral gavage. Tumor volumes and animal body weights were recorded. The results are summarized in Figures 6A-6B and Table 4 (assessed on day 13).

[0199] [Table 4] Although the G12C inhibitor AMG510 significantly inhibited tumor growth (T / C: 46%, p<0.001), compound (1) showed limited antitumor activity even at a dose of 80 mg / kg (T / C: 75%, p<0.01). Significant synergy was observed (T / C: 28%, p<0.05 vs. AMG510 alone, p<0.001 vs. compound (1) treatment alone). In addition, body weight changes were limited throughout the study period, indicating that compound (1) was well tolerated as a single agent or in combination with AMG510.

[0200] [Example 9] Evaluation of the antitumor activity of compound (1) in nude mice bearing KRAS_G12D, PIK3CA_H1047R, and PTEN_I67K mutant LS180 human colon tumor xenografts Oncogenic KRAS mutations are diverse and include not only G12C but also G12X and G13X at the mutation hotspot glycine at position 12. To determine whether compound (1), which targets downstream of MAPK and PI3K signaling, is effective against G12D mutant cancers, efficacy experiments of compound (1) were performed using subcutaneously implanted LS180 tumors derived from colon cancer with KRAS G12D and PIK3CA and PTEN gene alterations. The efficacy of compound (1) at 80 mg / kg / day was evaluated by comparing it with that of the MEK inhibitor trametinib at 1 mg / kg / day, which was used as the reference group. The results are presented in Figures 7A-7B and Table 4 (assessed on day 15).

[0201] [Table 5] Compound (1) showed modest but significant antitumor efficacy (T / C: 59%, p<0.01) and was well tolerated, whereas trametinib, which inhibits MAPK signaling activated by KRAS mutations, showed insufficient efficacy (T / C: 76%, not significant by Dunnett's test). These results suggest that MAPK inhibition alone may have limited efficacy in KRAS G12D mutant cancers with PIK3CA and / or PTEN gene alterations, whereas compound 1 showed superior efficacy and tolerability compared with MAPK signal inhibition alone.

[0202] [Example 10] Evaluation of the antitumor activity of compound (1) or trametinib or the combination of compound (1) and trametinib in nude mice bearing KRAS G12D mutant AsPC-1 human pancreatic tumor xenografts To investigate the antitumor efficacy of compound (1) against KRAS G12D mutant AsPC-1 human pancreatic tumors, compound (1) at 40 and 80 mg / kg / day, trametinib at 1 mg / kg / day, and a combination of compound (1) at 80 mg / kg / day and trametinib at 1 mg / kg / day were administered to male BALB / c nude mice subcutaneously implanted with AsPC-1 tumor xenografts for 3 weeks. All treatments were administered daily by oral gavage. Tumor volumes and animal body weights were recorded. The results are summarized in Figures 8A-8B and Table 6 (assessed on day 22).

[0203] [Table 6] Trametinib showed significant inhibition of tumor growth (T / C: 51%, p<0.001), whereas compound (1) showed limited antitumor activity in both the 40 and 80 mg / kg / day groups (T / C: 91%, not significant; T / C: 69%, p<0.01, respectively). Of note, significant synergy was observed (T / C: 26%, p<0.001 vs. trametinib alone, p<0.01 vs. compound (1) group at 40 mg / kg / day). A non-drug-related death was observed on day 18 in the compound (1) group due to a dosing error, but no significant changes in weight loss or tolerability were observed.

[0204] [Example 11] Evaluation of the growth inhibitory activity of compound (1), trametinib, and AMG510 against KRAS mutant cell lines used in animal studies The IC50 values ​​for each compound in the cell lines used in a series of animal studies evaluating the antitumor activity of compound (1) against KRAS mutant tumor xenografts were determined by a 3-day growth inhibition assay (Table 7).

[0205] [Table 7] Compound (1) showed relatively stable growth inhibitory effects against KRAS mutant cancer cell lines, whereas the growth inhibitory effects of trametinib and AMG510 were significantly attenuated in cells harboring mutations in the PIK3CA and PTEN genes (SW1573 and LS180). These findings are consistent with the relative responses of compound (1) to AMG510 and trametinib observed in efficacy studies.

[0206] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein.

Claims

1. 1. A pharmaceutical composition for treating a patient having a solid tumor with an abnormality in NF1, comprising an effective amount of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the solid tumor is at least one selected from the group consisting of breast cancer, lung cancer, ovarian cancer, skin cancer, colon cancer, liver cancer, and esophagogastric cancer.

3. The pharmaceutical composition of claim 2, wherein the solid tumor is breast cancer.

4. The pharmaceutical composition according to claim 3, wherein the breast cancer is human epidermal growth factor receptor 2-negative (HER2-) breast cancer.

5. 10. The pharmaceutical composition of claim 1, wherein the patient is determined to have an abnormality in NF1 prior to administering TAS0612 or a pharmaceutically acceptable salt thereof.

6. 2. The pharmaceutical composition of claim 1, wherein the solid tumor has a co-occurring abnormality in NF1 and at least one selected from the group consisting of KRAS, BRAF, PIK3CA, AKT1, and PTEN.

7. The pharmaceutical composition of claim 1 , wherein the solid tumor harbors an inactivating NF1 gene mutation.

8. 10. The pharmaceutical composition of claim 1, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered orally to the patient.

9. 10. The pharmaceutical composition of claim 1, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient once daily (QD).

10. 10. The pharmaceutical composition of claim 1, wherein about 10 to about 960 mg of TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient per day.

11. 10. The pharmaceutical composition of claim 1, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient daily for at least 28 days.

12. 1. A pharmaceutical composition for treating patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ / HER2-) breast cancer, comprising an effective amount of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharmaceutically acceptable salt thereof, in combination with a second breast cancer therapy.

13. The pharmaceutical composition of claim 12, wherein the second breast cancer therapy is at least one selected from the group consisting of endocrine therapy, cell cycle inhibitor therapy, and radiation therapy.

14. 14. The pharmaceutical composition of claim 13, wherein the second breast cancer therapy is endocrine therapy using tamoxifen and / or fulvestrant.

15. 14. The pharmaceutical composition of claim 13, wherein the second breast cancer therapy is a cell cycle inhibitor therapy using abemaciclib, palbociclib, and / or ribociclib.

16. The pharmaceutical composition of claim 13 , wherein the second breast cancer therapy is radiation therapy.

17. The pharmaceutical composition of claim 12, wherein the HR+ / HER2- breast cancer is recurrent or refractory HR+ / HER2- breast cancer.

18. 18. The pharmaceutical composition of claim 17, wherein the patient with the recurrent or refractory HR+ / HER2- breast cancer has already received endocrine therapy and / or a therapeutic regimen with a cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor prior to the step of administering TAS0612 or a pharmaceutically acceptable salt thereof.

19. 19. The pharmaceutical composition of claim 18, wherein the recurrent or refractory HR+ / HER2- breast cancer has acquired resistance or refractory to endocrine therapy and / or a therapeutic regimen using a cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor.

20. The pharmaceutical composition of claim 17, wherein the recurrent or refractory HR+ / HER2- breast cancer is endocrine therapy resistant.

21. The pharmaceutical composition of claim 17, wherein the recurrent or refractory HR+ / HER2- breast cancer is tamoxifen-resistant and / or fulvestrant-resistant.

22. The pharmaceutical composition of claim 17, wherein the recurrent or refractory HR+ / HER2- breast cancer is resistant to a CDK4 / 6 inhibitor.

23. The pharmaceutical composition of claim 12, wherein the HR+ / HER2- breast cancer harbors an abnormality in NF1.

24. 13. The pharmaceutical composition of claim 12, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered orally to the patient.

25. 13. The pharmaceutical composition of claim 12, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient once daily (QD).

26. 13. The pharmaceutical composition of claim 12, wherein about 10 to about 960 mg of TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient per day.

27. 13. The pharmaceutical composition of claim 12, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient daily for at least 28 days.

28. 1. A pharmaceutical composition for treating a patient having a cancer associated with an abnormality in PTEN, comprising an effective amount of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharmaceutically acceptable salt thereof.

29. 29. The pharmaceutical composition of claim 28, wherein the cancer is at least one selected from the group consisting of breast cancer, thyroid cancer, renal cell carcinoma, endometrial cancer, colorectal cancer, melanoma, glioblastoma, prostate cancer, ovarian cancer, and lung cancer.

30. 29. The pharmaceutical composition of claim 28, wherein the cancer is endometrial cancer.

31. 29. The pharmaceutical composition of claim 28, wherein the patient is determined to have an abnormality in PTEN prior to administering TAS0612 or a pharmaceutically acceptable salt thereof.

32. 29. The pharmaceutical composition of claim 28, wherein the cancer has a co-occurring abnormality in PTEN and at least one selected from the group consisting of KRAS, BRAF, PIK3CA, AKT1, EGFR, HER2, TP53, NF1, and BRCA.

33. 29. The pharmaceutical composition of claim 28, wherein the cancer has co-occurring abnormalities in PTEN and PIK3CA.

34. 29. The pharmaceutical composition of claim 28, wherein the abnormality in PTEN is a PTEN gene defect or a mutation that results in loss of function.

35. 29. The pharmaceutical composition of claim 28, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered orally to the patient.

36. 29. The pharmaceutical composition of claim 28, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient once daily (QD).

37. 29. The pharmaceutical composition of claim 28, wherein about 10 to about 960 mg of TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient per day.

38. 29. The pharmaceutical composition of claim 28, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient daily for at least 28 days.

39. 1. A pharmaceutical composition for treating patients with cancer having an abnormality in KRAS, comprising an effective amount of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition of claim 39, wherein the cancer is at least one selected from the group consisting of colorectal cancer, lung cancer, pancreatic cancer, endometrial cancer, skin cancer, ovarian cancer, bile duct cancer, and breast cancer.

41. 40. The pharmaceutical composition of claim 39, wherein the patient is determined to have an abnormality in KRAS prior to administering TAS0612 or a pharmaceutically acceptable salt thereof.

42. 40. The pharmaceutical composition of claim 39, wherein the cancer has a co-occurring abnormality in KRAS and at least one selected from the group consisting of BRAF, PIK3CA, PTEN, EGFR, TP53, BRCA, APC, MTOR, and SMAD4.

43. 40. The pharmaceutical composition of claim 39, wherein the cancer has co-occurring abnormalities in KRAS and at least one selected from the group consisting of PIK3CA and PTEN.

44. 40. The pharmaceutical composition of claim 39, wherein the cancer harbors a KRAS G12C mutation or a KRAS G12D mutation.

45. 45. The pharmaceutical composition of claim 44, wherein the patient is administered TAS0612, or a pharmaceutically acceptable salt thereof, in combination with a KRAS G12C-specific inhibitor or a KRAS G12D-specific inhibitor.

46. 40. The pharmaceutical composition of claim 39, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered orally to the patient.

47. 40. The pharmaceutical composition of claim 39, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient once daily (QD).

48. 40. The pharmaceutical composition of claim 39, wherein about 10 to about 960 mg of TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient per day.

49. 40. The pharmaceutical composition of claim 39, wherein TAS0612 or a pharmaceutically acceptable salt thereof is administered to the patient daily for at least 28 days.

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